RAS inhibitors

Abstract

The present disclosure features macrocyclic compounds capable of inhibiting Ras proteins, as well as pharmaceutical compositions and protein complexes thereof, and their use in cancer treatment.

Description

Technical field

[0001] See mutual reference of related applications This application was filed on November 4, 2019, the US Patent No. 62 / 930, 394; applied on December 20, 2019, 62 / 951,763; applied on March 26, 2020.In the same way, the interests of the priority on the 633 / 043,601, which were filed on June 24, 2020, are asserted, and all of these are all incorporated into the Honemin Dote by reference.。 [Background technology]

[0002] The overwhelming majority of low molecular drugs act by binding to a target protein and functionally important, which controls the activity of the protein.For example, cholesterol lower agents, known as status, bind them to the enzyme activity site of HMG-COA Redactase, so the enzyme prevents them from interacting with their substrates.The fact that many such drugs / target interaction pairs are known is that, in consideration of a certain amount of people and the reasonable time, efforts, and the amount of resources, the low molecular modulator is not all.It could believe that most proteins can be found.This is far from the fact.It is the current estimation that only about 10%of all of all of the human proteins can be targeted by low molecules.BOJADZIC AND BUCHWALD, CURR TOP MED CHEM 18: 674-699 (2019).Other 90%are now considered to be inappropriate or intractable to the low molecular drug discovery described above.Such a target is generally called "Andrugabble".These Andrugable targets include a vast, large, unused reservoir with a clinically important human protein.Therefore, there is a lot of interest in discovering new molecular modalities that can control such a target function of such an implanted target.

[0003] RAS proteins (K-RAS, H-Ras, and N-Ras) play an indispensable role in various human cancer, so it is enough to be appropriate for anticancer treatment.It has been established.In fact, mutations in RAS proteins account for about 30%of all human cancer in the United States, and many of them are lethal.Adjustment of RAS proteins due to mutation activation, over -expressed, or upstream expression is common in human tumors, and the activation of mutations in RAS is frequently discovered in human cancer.For example, the activation of mutations in codon 12 in RAS proteins inhibits both GTPase activation proteins (GAP) dependence and inherent hydrolysis speeds in GTP, and "on" (GTP "(GTP)It works by significantly distorted to (Ras (ON)) and a carcinogenic MAPK signal transmission.In particular, RAS shows picomol affinity against GTP, and enables RAS to be activated even in the presence of this low -concentration nucleotide.The mutation (eg, G13D) in the Ras codon 13 and the mutation in codon 61 (eg, Q61K) also have the carcinogenic activity in some cancers.

[0004] In recent decades, RAS has made large -scale drug discovery efforts, but no drugs that directly target RAS have been approved.Further efforts are required to clarify additional drugs for cancer driven by various RAS mutations. [Overview of invention]

[0005] Ras inhibitors are provided in the current note.The approach described in this book is two -in -cell proteins that do not interact under synthetic ligand and normal physiological conditions: target proteins (eg, RAS), and the site that is widely expressed in cells.(Presentation protein) (for example, cyclophyllin A) requires the formation of a high -viney component complex.More specifically, in some embodiments, the RAS inhibitors described in this book are highly relative between RAS proteins and Cyclophilin A (Cypa), a wide range of sites, Sol Shas Caston.Includes a new binding pocket site d in RAS by driving the formation of a sex bird complex.Although it is not bound by the theory, the method that is affected by the inhibitory effect on the RAS by the compound and complex of the present invention is interaction between RAS and downstream effector molecules such as RAF and PI3K.The present inventor believes that the three -dimensional obstruction of the site is formed, which is necessary to grow the carcinogenic signal.

[0006] Therefore, in some embodiments, the present disclosure is characterized by the compound of structural type I or its pharmaceutically acceptable salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of the 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Allelen, or arbitrarily replaced 5 ~ 10.It is bonded to the carbon atom of the Hetero Allylene.] B does not exist, -ch (r) 9 )-or> C = CR 9 R 9’ [In the formula, carbon is -n (r) 11 C (o)-, 3 to 6 cycloalene, arbitrarily replaced, 3 to 6 heterocycloalene, six Alrain, or 5-6 members.It is bonded to the heteroseurelene carbonyl carbon.] G is an arbitrarily replaced C 1 -C 4 Alkylene, arbitrarily replaced C 1 -C 4 Alkenylene, arbitrarily replaced C 1 -C 4 Heterocyulene, -c (o) o-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], -C (o) nh-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], C in arbitrarily replaced 1 -C 4 Heterocyulene or 3-8 heteralen, L does not exist, or a linker, W is hydrogen, cyano, S (o) 2 R ', arbitrarily replaced amino, arbitrarily replaced amide, arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. X 1 Is an arbitrarily replaced C 1 -C 2 Alkylene, NR, O, or S (O) n , X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 CH, CH 2 , Or N, Y 6 C (o), ch, ch 2 , Or N, R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 Alyl or hetereril of 5 to 10 members that are arbitrarily replaced R 1 And R 2 Forms a heterocycloalchill for 3 to 14 members that are arbitrarily replaced with the bonded atoms. R 2 Do not exist, hydrogen, arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 6 cycloalkyl, arbitrarily replaced 3 to 7 heterocycloalkyl, six arils of arbitrarily replaced, 5 or 6 Hetero.Alyl, R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7a And R 8a Is independent, hydrogen, halo, arbitrarily replaced c 1 -C 3 It is alkyl or combined with the carbon in which they bind, forming carbonyyl. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Hydrogen, F, arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, arbitrarily replaced cycloalual kill, or heterocycloalkyl of 3 to 7 members that are arbitrarily replaced. R 9 And L forms a heterocycloalkyl for 3 to 14 members that are arbitrarily replaced with the atoms they bind. R 9’ Is hydrogen or arbitrarily replaced c 1 -C 6 Alkyl, R 10 Is hydrogen, halo, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, R 10a Is hydrogen or halo, R 11 Is hydrogen or c 1 -C 3 Alkyl.It also provides a compound of equation I, or a pharmaceutical composition, which is a pharmaceutically acceptable salt, and a pharmaceutically acceptable levy agent.And R 16 Is hydrogen or c 1 -C 3 Alkyl (for example, methyl).].

[0007] The treatment method of cancer in the subject that requires cancer treatment is the above -mentioned method of the compound of the present invention that is effective for treatment, or the pharmaceutical salt.The above method, including what to do, is also provided.

[0008] In some embodiments, it is a treatment method for RAS protein -related diseases in the subject that requires the treatment of RAS protein -related diseases.Alternatively, provide the above method, including the administration of the pharmaceutically acceptable salt.

[0009] It is a method of inhibiting RAS proteins in cells, and further provides the above method, including the above method, including the above -mentioned cells in contact with the compounds of the effective amount of the present invention or their pharmaceutical salt.do.

[0010] It is specifically imagined that all limitations that are discussed on the embodiment of the present invention may be applied to any other embodiment of the present invention.Furthermore, any compound or composition of the present invention can be used in any method of the present invention, and any method of the present invention is used to generate or use any compound or composition of the present invention.can do. [Simple explanation of drawing]

[0011] [Fig. 1A] Compound a, a compound of the present invention, indicates a PK-dependent RAS route control in the CAPAN-2 CDX model (PDAC, KRAS G12V / WT).The second dose of compound A, which was delivered 8 hours after the first dose, (shown with a black arrow).All dose levels are fully acceptable.All dose levels are fully acceptable.The expression of the tumor DUSP6 MRNA as a parent of contrast, displayed with a stick on the Y -axis on the left.The dotted line indicates the return to DUSP6 at the control level.Unconjected plasma PK (NM), which is plotted on the Log10 scale on the Y -axis on the right, displayed on the graph as a line.N = 3 / time.The error bar represents the standard error of the average value. [Fig. 1B] CAPAN-2 CDX models (PDAC, KRAS G12V / WT), combinatorial antitumor activity with compound A, a compound of the present invention, and inhibiting upstream SHP2.Capan-2 cells were injected into 50% MATRIGEL.Animals were random and treatment was started with an average of about 180 mm3 average tumor volume.For 40 days, the combination of SHP2 inhibitor RMC-4550 (20mg / kg PO Q2D), compound A 100mg PO BID, RMC-4550 combination, or contrast.All dose levels were allowed.N = 10 / group (in the combination group, n = 9).NS = no significant difference; *** <0.001 by uniform ANOVA. [Form for implementing inventions]

[0012] Definition and chemical terms In this application, unless it is exceptionally clear from the context, (i) term "one (a)" means "one or more", (II) means only alternative expressions, or or relevant.Unless the alternative expression is clearly exclusive, it is used to mean "and / or", but the present disclosure only referred to the alternative expression and " / or".Supporting the definition, (III) terminology "contains (comprising)" and "include" are presented by them themselves or with one or more additional components or processes.It is understood that the components or processes of the components or processes that are specified by item are included, and the end point is included when the (IV) range is shown.

[0013] When used in the spectrum book, the term "about" is used to indicate that the value is the standard deviation of the error of the device or method used to determine the value.According to a specific embodiment, the term "about" is not described separately or unless it is clear from the contents separately (for example, if it can exceed 100%of the possible value).In any direction (exceeding or lower), 25%, 20%, 19%, 18%, 17%, 17%, 16%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%or less.

[0014] When used in the spectrum, the term "adjacent" in the context describing the adjacent atoms means a dual atom that is directly bonded by a shared bond.

[0015] When used in the spectrum, the compounds of the present invention and the similar terms are described as explicitly, and the compounds of the equation I, their sub -type, and the Table 2 and Table 2.Compounds, in addition, their salt (for example, pharmaceutically acceptable salt), solvent Japanese, hydrogen, three -dimensional straps (including atrop straps), and substantial heterogeneous.It means the RAS inhibitor described in.

[0016] The term "wild type" means a structure or activity that is found in nature (a pair of normal "(pair of variants, diseases, changes, etc.) in nature or a structure or activity found in context.The artist will understand that wild gene and polypeptide are often in multiple different forms (for example, allel).

[0017] Some compounds described in this book are one or more (eg, three -dimensional hypotonies, geometric hom, atrop anetometric body, subdivision bodies), or aretable (eg, heavy hydrogen).The art will understand that one or more atoms, such as hydrogen replaced by, can exist in the form of a different isotope of the atom.Unless otherwise specified, or unless it is clear from the context, it can be understood that the described structure indicates an individual or combination of such anometics or isotope.

[0018] The compounds described in this book can be asymmetric (for example, having one or more solid central).All three -dimensional straps, such as Enachi Omar and Zia Stereomer, are intended unless specified specifically.The compounds of the book provided containing a carbon atom asymmetric can be isolated in an optical active form or lacemi body.It is known in this technical field to prepare an optical active form from an optical activity, such as split or three -dimensional selection method.Many geometric fluids such as olefin and c = n double bonds can also exist in the compounds described in the present disclosure, and all such stable heteroses are expected in the present invention.The cis and transformer of the transformer of the main disclosure are described, and can be isolated as a mixture of the opposite body or as a separated heterosexual.

[0019] In some embodiments, one or more compounds described in the present book can exist in a different form of heterogeneous forms.Unless it is explicitly excluded, such compounds include all of these different types of heterogeneous forms, as clarified from the context.In some embodiments, a subdivision of the heterogeneous form is caused by replacing a single combination with an adjacent double bond, and the movement of the accompanying proton.In a specific embodiment, the comparative heterogeneous form can be a prototropy subdivision, which is the same as the reference form and the protonization state of the opposite body that has the same charge.Examples of the part with a prototropy subdivision form are ketone-enolpea, amide-imidate pair, lactam-lactim pair, amide-imidate pair, enamine-imidate, and 1h- and 3H-imidazole, 1h-, 2h, 2H, 2h.-, And 4H-1,2,4-Triazole, 1H-and 2H-Ishin dolls, and the proton, such as 1h- and 2H-Pilazole, occupy two or more locations in the complex ring system.It is a format form that can be done.In some embodiments, the comparative hypotonal forms can be fixed in a three -dimensional format by equilibrium or appropriate substitutions.In a specific embodiment, a substantial heterogeneous form is caused by an acetal interconnection.

[0020] Unless otherwise specified, the structure shown in this specification also means that only one or more istock -based enrichment atoms contain different compounds.As an exemplary isotope that can be incorporated into the compounds of the present invention, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 CL, 123 I and 125 Characters, such as I and other hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, are listed.Countermarked compound (eg,, 3 H and 14 The compound indicated by C can be useful in the compound or substrate tissue distribution assay.Tritium sign (that is, 3 H), and carbon 14 (that is, 14 C) The isotope can be useful because of the ease of preparation and detection.Furthermore, heavier isotopic, for example, heavy hydrogen (that is, 2 Replacement by H), etc., the metabolic stability increases, resulting in a specific therapeutic advantage (eg, the half -period of the Invivobo half -year, or the required amount of medication is reduced).In some embodiments, one or more hydrogen atoms 2 H or 3 Whether it is replaced by H or one or more carbon atoms 13 C or 14 C Replaced by concentrated carbon. 15 O, 13 N, 11 C and 18 Positron release isotopes such as F are useful for Positron Releasefall (PET) research for inspection of substrate receptor occupation.The preparation of the isotoped compounded compound is known to the art.For example, the isotope -labeled compound is generally replaced with a reagent that is not an isotoped -based reagent, in general, in accordance with the procedure that is similar to the procedure disclosed to the compounds of the present invention described in the present book.Can be prepared by.

[0021] As is known in conventional technology, many chemical components can be adopted in various different types of solid forms, for example, a non -crystal or crystal form (eg, hydrate, solvent Japanese).In some embodiments, the compounds of the present invention can be used in any form, including any solid form.In some embodiments, the compounds described or described in this book can be provided or used in a hydrate or solvent Japanese form.

[0022] In various parts of the present text, the substituents of the main disclosure compound are disclosed in a group or range.It is specifically intended to contain the present disclosure of each individual partial combination of each of these groups and range members.For example, the term "c 1 -C 6 "Alkyl" is specifically, methyl, ethyl, and c 3 Alkyl, C 4 Alkyl, C 5 Alkyl, and C 6 The intention is to disclose alkyl individually.Furthermore, if the compound contains multiple positions in which the substituent is disclosed in a group or range, the present disclosure contains the sub -combination of each, and in each position in each position.It is intended to extend to an individual compound and a group of compounds (for example, genus and lower genus).

[0023] The term "X" (for example, arbitrarily replaced alkyl) is "X, X is arbitrarily replaced" (for example, "alkyl, the alkyl above alkyl is optional.It is intended to be equal to).Features "X" (for example, alkyl) itself does not mean that it is an arbitrary one.As described in this statement, a certain compounder that is subject to one or more can contain one or more "arbitrarily replaced" portion.Normally, the term "replaced" is a replacement group that is suitable for one or more hydrogen of the specified part, for example, the replacement described in the present detail, regardless of whether or not the term "arbitrarily" comes first.It means that it is replaced by the group or the base.Unless otherwise specified, a "arbitrarily replaced" group may have a suitable substituent at each suitable position.Further, if two or more positions in an arbitrary structure can be replaced by two or more substituents selected from a specific base, the substituent is the same or different in each position.You may be either.For example, the term "arbitrarily replaced c 1 -C 6 Alkyl-C 2 -C 9 In the "heteroaryl", both alkyl, hetereryl, or this may be arbitrarily replaced.The combination of the substituents that are imagined by the present disclosure is preferably obtained by the formation of a stable or chemically suitable compound.When used in the present invention, the term "stable" is used for the production, detection of compounds, and in a specific embodiment for one or more purposes disclosed in the recovery, purification, and the present details.When using a condition in anticipation of use, it means a compound that does not actually change.

[0024] In the carbon atom that can be replaced by "arbitrarily replaced" groups, the preferred substituent is independent, heavy hydrogen, halogen, (ch (ch "CH). 2 ) 0 - 4 R °,-(ch 2 ) 0 - 4 Or °, -o (ch (ch) 2 ) 0 - 4 R ° , -O- (ch 2 ) 0 - 4 C (o) or °,-(ch 2 ) 0 - 4 Ch (or °) 2 ,-(ch 2 ) 0 - 4 SR °,-(ch 2 ) 0 - 4 PH [R ° may be replaced.],-(ch 2 ) 0 - 4 O (ch 2 ) 0 - 1 PH [R ° may be replaced.], -CH = chpH [R ° may be replaced.],-(ch 2 ) 0 - 4 O (ch 2 ) 0 - 1 -Pyrizil [may be replaced by R °.], 4 to 8 saturated or unsaturated heterocycloalkill (eg, pyrizil), 3 to 8 saturated or indes an intensity cycloalkill (for example, cyclopropyl, cyclobotenill), -no 2 , -Cn, -n 3 ,-(ch 2 ) 0 - 4 N (R °) 2 ,-(ch 2 ) 0 - 4 N (r °) c (o) r °, -n (r °) c (s) r °,-(ch 2 ) 0 - 4 N (r °) c (o) nr ° 2 , -N (r °) c (s) NR ° 2 ,-(ch 2 ) 0 - 4 N (r °) c (o) or °, -n (r °) n (r °) c (o) r °, -n (r °) n (r °) n (o) nR ° 2 , -N (r °) n (r °) c (o) or °,-(ch 2 ) 0 - 4 C (o) r °, -c (s) r °,-(ch 2 ) 0 - 4 C (o) or °,-(ch 2 ) 0 - 4 -C (o) -n (r °) 2 ,-(ch 2 ) 0 - 4 -C (o) -n (r °) -s (o) 2 -R °, -c (NCN) NR ° 2 ,-(ch 2 ) 0 - 4 C (o) sr °,-(ch 2 ) 0 - 4 C (o) osir ° 3 ,-(ch 2 ) 0 - 4 OC (O) R °, -OC (O) (ch 2 ) 0 - 4 SR °, -sc (s) SR °,-(ch 2 ) 0 - 4 Sc (o) r °,-(ch 2 ) 0 - 4 C (o) nr ° 2 , -C (s) NR ° 2 , -C (s) sr °,-(ch 2 ) 0 - 4 OC (O) NR ° 2 , -C (o) n (or °) r °, -c (o) r °, -c (o) chh 2 C (o) r °, -c (nor °) r °,-(ch 2 ) 0 - 4 SSR °,-(ch 2 ) 0 - 4 S (O) 2 R °,-(ch 2 ) 0 - 4 S (O) 2 Or °,-(ch 2 ) 0 - 4 OS (O) 2 R °, -s (o) 2 NR ° 2 ,-(ch 2 ) 0 - 4 S (o) r °, -n (r °) s (o) 2 NR ° 2 , -N (r °) s (o) 2 R °, -n (or °) r °, -c (nor °) NR ° 2 , -C (nh) NR ° 2 , -P (O) 2 R °, -p (o) r ° 2 , -P (o) (or °) 2 , -Op (o) r ° 2 , -OP (o) (or °) 2 , -OP (o) (or °) r °, -sir ° 3 ,-(C 1 - 4 Direct chain or branch chain alkylene) o-n (r °) 2 Or,-(c 1 - 4 Direct chain or branch chain alkylene) c (o) o-n (r °) 2 In the formula, each R ° may be replaced so that it is defined in the following, independent, hydrogen, -c. 1 - 6 Peppers, -ch 2 PH, -o (ch 2 ) 0 - 1 PH, -ch 2 -(5-6 heterierl ring), or 3 to 6 heterometry, which has 0 to 4 hetero atoms selected independently from nitrogen, oxygen, or sulfur, 3 to 6 members, saturation, partial unsaturated.Or the two R °, which exists independently, or independent of nitrogen, oxygen, or sulfur, together with the atoms (multiple possible) in between.The saturation, partial unsaturated, or an aryl single or two -ring ring of 3 to 12 members with 0 to 4 hetero atoms may be substituted as defined in the following.。

[0025] A suitable value replacement group on r ° (or in between using two independent R ° in the middle) is independent, halogen, (ch (ch) 2 ) 0 - 2 R ● ,-(Halo R ● ),-(CH 2 ) 0 - 2 OH,-(ch 2 ) 0 - 2 Or ● ,-(ch 2 ) 0 - 2 Ch (or ● ) 2 , -O (Halo R ● ), -Cn, -n 3 ,-(ch 2 ) 0 - 2 C (o) r ● ,-(ch 2 ) 0 - 2 C (o) oh,-(ch 2 ) 0 - 2 C (o) or ●,-(ch 2 ) 0 - 2 Sr ● ,-(ch 2 ) 0 - 2 SH,-(ch 2 ) 0 - 2 NH 2 ,-(ch 2 ) 0 - 2 NHR ● ,-(ch 2 ) 0 - 2 NR ● 2 , -No 2 , -Sir ● 3 , -OSIR ● 3 , -C (o) sr ● ,-(C 1 - 4 Direct chain or branch chain alkylene) c (o) or ● , Or -ssr ● In the formula, each R ● Is a non -substitution or a place where "halo" is first attached, and is replaced only by one or more halogen, and is independent. 1 - 4 Peppers, -ch 2 PH, -o (ch 2 ) 0 - 1 It is selected from the saturation, partial unsaturated, or arel -ring of 5 to 6 members, with 0 to 4 heterometrons selected independently from pH, or nitrogen, oxygen, or sulfur.= O and = S are the preferable dual substituents on the saturated carbon atom of R °.

[0026] The preferable dual substituents on the "arbitrarily replaced" group are: = o, = s, = nnr * 2 , = NNHC (O) R * , = NNHC (O) or * , = NNHS (O) 2 R * , = NR * , = NOR * , -O (C (r) * 2 ) 2 - 3 O-, or -s (C (r) * 2 ) 2 - 3 S- is listed and exists independently during the ceremony * Can be replaced so that hydrogen is defined in the following C. 1 - 6 Selected from the saturation, partial, or aryl ring of 5 to 6 non -substituents, which have 0 to 4 heterogomic atoms selected independently from pipousons, nitrogen, oxygen, or sulfur.。A suitable dual substituent that binds to a vicinal replacement carbon of a "arbitrarily replaced" group -o (CR) * 2 ) 2 - 3 O- is listed and exists independently during the ceremony * Can be replaced so that hydrogen is defined in the following C. 1 - 6 Selected from the saturation, partial, or aryl ring of 5 to 6 non -substituents, which have 0 to 4 heterogomic atoms selected independently from pipousons, nitrogen, oxygen, or sulfur.。

[0027] R * The suitable substituent on the pepper group is -R ● , (Halo R ● ),-Oh, -or ● , -O (Halo R ● ), -Cn, -c (o) oh, -c (o) or ● , -Nh 2 , -Nhr ● , -Nr ● 2 , Or -no 2 In the formula, each R ● Is a non -substitution or a place where "halo" is first attached, and is replaced only by one or more halogen, and is independent. 1 - 4 Peppers, -ch 2 PH, -o (ch 2 ) 0 - 1 The saturation, partial, or aryl ring of 5 to 6 members, which have 0 to 4 heterometrons selected independently of pH, or nitrogen, oxygen, or sulfur independently.

[0028] A suitable substituent on nitrogen that can be replaced by a "arbitrarily replaced" group, is -r † , -Nr † 2 , -C (o) r † , -C (o) or † , -C (o) c (o) r † , -C (o) ch 2 C (o) r † , -S (o) 2 R † , -S (o) 2 NR † 2 , -C (s) NR † 2 , -C (nh) NR † 2 , Or -n (r) † ) S (O) 2 R † In the formula, each R † Is independent, can be replaced so that it is defined in the following hydrogen. 1 - 6 The saturated, partial unsaturated, or partial unsaturated 3 to 6 non-substitutions, with 0 to 4 heterocomiers selected independently from pepper, non-substitution, or nitrogen, oxygen, or sulfur.The two R, which exists independently, regardless of the alill ring or regardless of the definition above † Is a saturated, partial unsaturated 3 to 12 non -substitution, with 0 to 4 hetero atoms selected independently from nitrogen, oxygen, or sulfur, along with the atoms (multiple) in the meantime., Or form an aryl or a two -ring ring.

[0029] R † The suitable substituents on the pepper group are independent, halogen, -R ● ,-(Halo R ● ),-Oh, -or ● , -O (Halo R ● ), -Cn, -c (o) oh, -c (o) or ● , -Nh 2 , -Nhr ● , -Nr ● 2 , Or -no 2 In the formula, each R ● Is a non -substitution or a place where "halo" is first attached, and is replaced only by one or more halogen, and is independent. 1 - 4 Peppers, -ch 2 PH, -o (ch 2 ) 0 - 1 The saturation, partial, or aryl ring of 5 to 6 members, which have 0 to 4 heterometrons selected independently of pH, or nitrogen, oxygen, or sulfur independently.R † = O and = S are the preferable dual substituents of the saturated carbon atom.

[0030] When used in the current note, the term "acetyl" is the base-c (o) ch. 3 Is.

[0031] When used in the current note, the term "alcohoxy" is -o-c 1 -C 20 In terms of alkyl, alcohoxy group binds to the remaining part of the compound via oxygen atom.

[0032] When used in this book, the term "alkyl" is 1 to 20 (for example, 1 to 10, or 1 to 6), which contains carbon, the amount of carbon of the amount of the amount of worthless, direct chain or branch chain.It means a hydrogen group.In some embodiments, the alkyl group is a non -branch chain (that is, direct chain), and in some embodiments, the alkyl group is a branch chain.The alkyl group is exemplified by methyl, ethyl, N- and isopyl, N-, SEC-, iso and tert-butyl, and Neopentil, but is not limited.

[0033] When used in this specification, the term "alkylene" represents a dual hydrocarbon group of dialogue derived from direct -chain or branched -chain saturated hydrocarbons by removing two hydrogen atoms, and is methylene and ethylene., Examinated by isopropylene.Terminology "C x -C y "Alkylene" represents an alkylene group having an x ~ y carbon.The example value of X is 1, 2, 3, 4, 5, and 6, and the exemplary value of y is 2, 3, 4, 6, 7, 7, 9, 10, 12, 14., 16, 18, or 20 (for example, C 1 -C 6 , C 1 -C 10 , C 2 -C 20 , C 2 -C 6 , C 2 -C 10 , Or C 2 -C 20 Alkylene).In some embodiments, alkirene can be further replaced by 1, 2, 3, or four substituents, as defined in the present book.

[0034] When used in the book, the term "Alkenyl" is 2 to 20 carbon containing one or more carbon-carbon double bonds (eg, 2 to 6, or 2 to 10, unless specified specified in particular.Individuals are represented by ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl, which represents a priced liner or branch chain group of an individual carbon).Alkenyl contains both sis and transformatives.When used in the book, the term "Alkenylene" is 2 to 20 carbon containing one or more carbon-carbon double bonds (eg, 2 to 6, or 2 to 10, unless specified specified.Individual carbon represents a double -prone or branch chain group.

[0035] When used in the book, the term "alkinyl" is based on 2 to 20 carbon atoms (for example, 2-4, 2 to 6, or 2 to 10 carbon) containing carbon-carbon triple bonds., Expected a priced direct chain or branch chain group, and is illuminated by ethinyl and 1-propiny.

[0036] When used in the books, the term "alkinylsulphone" is a structure. [Formation] [In the formula, R is an arbitrary substituent suitable for chemicals described in the book.She represents a group containing.

[0037] When used in the present book, the term "amino" is -n (r) † ) 2 For example, -nh 2 And -n (CH) 3 ) 2 Is shown.

[0038] When used in the spectrum, the term "amino alkyl" represents an alkyl part replaced by one or more amino parts on one or more carbon atoms.

[0039] The term "amino acid" described in this book is a side chain, amino group, and acid group (for example, -co 2 H or -SO 3 It means the molecule having H), and the amino acid is bonded to the boss -molecular group by side chains, amino groups, or acid groups (eg, side chains).When used in this specification, the most wide term "amino acid" means an arbitrary compound or substance that can be incorporated into a polypeptide chain by forming one or more peptide bonds.In some embodiments, amino acids are general structure H. 2 It has n-C (h) (r) -cooh.In some embodiments, amino acids are natural amino acids.In some embodiments, amino acids are synthetic amino acids, in some embodiments, amino acids are D-amino acids, and in some embodiments, amino acids are L-amino acids."Standard amino acids" means either of the 20 standard L-amino acids that are commonly found in peptides in nature.Examinated amino acids include alanine, arginine, asparagin, cysteine, glutamic acid, glutamine, glutamine, glycin, histidine, arbitrarily replaced hydroxylbalin, osoleysin, lysine, lysine, methionine, norbalin, phenylalinin, phenylalininThere are pylolicin, Sereno cystine, serine, taurine, toleonin, test fan, tyrosine, and balin.

[0040] When used in this book, the term "ary" represents a monetary, two -ring, or polygan -type ring system formed by a carbon atom, and the ring that binds to the pendant group is aromatic.It is.The example of the aryl group is phenyl, naphtile, fenantulenyl, and Anthracenyl.The aryl ring can be bonded to the pendant group in any terrorist or carbon human atom that brings a stable structure, and one of the winds can be voluntarily replaced unless specified specified.

[0041] When using it in the current note, "C" 0 Is a bond.For example, term-n (c (o)-(c) 0 -C 5 Alkylene-H)-Part of -N (c (o)-(c) 0 Including alkirene-h)-, this is also represented by -n (c (o) -h)-.

[0042] When used in the spectral book, the term "carbon ring" and "carboosyclill" means the single-ring, two-ring, or triple ring structure of the C3-C12 that is voluntarily replaced.However, this is arbitrarily cross -linked, controlled, or spilly, all rings are formed by carbon atoms, and at least one ring is non -aromatic.The carbon ring structure includes cycloalkill, cycloalkenyl, and cycloalkinyl group.Examples of carboosyclil groups include cyclohexyl, cyclohexenyl, cycloquatinyl, 1,2-dihydronaph chill, 1,2,3,4-tetrahidronafuchyl, full orenyl, indanil, and decalinyl.The carbon ring -style ring can be bonded to the pendant group in any environmental atoms that provide a stable structure, and one of the rims can be arbitrarily replaced unless specified specified.

[0043] When used in the book, the term "carbonyl" represents a C (O) group that can be represented as C = O.

[0044] When used in the current note, the term "carboxyl" is -co 2 H, (c = o) (oh), cooh, c (o) oh, or non -protonization.

[0045] When used in the book, the term "cyano" represents the -cn group.

[0046] When used in the book, the term "cycloalkyl" represents a priced saturated ring -based hydrocarbon group, and it is bridged, comparable, or 3 to 8 carbon.It is well -spilly, and is exemplified by cyclopropyl, cyclobotille, cyclopenyl, cyclohexyl, cyclo, and cyclo.

[0047] When used in this book, the term "cycloal kenyl" represents a paid non -aromatic saturated environmental hydrocarbon group, which is bridge, or 3 to 8 pieces unless specified specifically.It is good to be a spillo ring with carbon, and contains one or more carbon-carbon double bonds.

[0048] When used in the books, the term "giastereomer" means a three -dimensional strap that cannot be overlapped with each other, not a mirror image.

[0049] When used in this book, the "Enancho" is at least 80%(that is, at least one of the 90%Enancho, and another 10%of the Enancho Omar), at least 90%, and more preferablyIt means an individual optical activity form of the present invention, which has at least 98%of optical purity or a mirror image of anomeromer (measured in a standard method in the technical field).

[0050] The term "Guanidil" is a structure [Formation] [In the formula, each R is independent, and is an arbitrary chemical substituent described in the present book.] Is a base that has.

[0051] When used in the spectral book, the term "Guanidino Alkyl Alkyl" represents an alkyl part replaced by one or more guidelines on one or more carbon atoms.

[0052] When used in the book, the term "haloacetyl" means an acetyl group in which at least one hydrogen is replaced by halogen.

[0053] When used in the spectrum book, the term "Hello alkyl" represents an alkyl part that is replaced by one or more carbon atom in the same or different halogen.

[0054] When used in the edible book, the term "halogen" represents a halogen selected from chlorine, chlorine, iodine, or fluorine.

[0055] When used in the book, the term "heter alkill" is defined in the "alkyl" group (for example, O, N, or S atoms) that at least one carbon atom is replaced with hetero atoms (eg, O, n, or S atoms).It refers to).Heteromic atoms can appear in the center or end of the radical.

[0056] When used in this specification, the term "heterieryl" represents a monitor -type or multi -ring -style circular structure containing at least one complete aromatic ring.That is, these contain 4N+2 π electrons in the single -ring or polygan -type ring system, and contain terrorist atom in the aromatic ring selected from N, O or S.do.Executive non -substituted heteroalyl groups are carbon of 1 to 12 (for example, 1-11, 1 ~ 10, 1 ~ 9, 2 ~ 12, 2 ~ 11, 2 ~ 9).It is.The term "heteroaryl" is a two -ring, three ring, and quadratic group, which is a rectic, and a carbon circular ring, for example, a hetero -aroming ring, for example, a phenyl or cyclohexan ring.including.Examples of the hetereryl group include pyrizil, pyrazolille, benzo chocolate rill, benzoomidazorill, benzoch anzolille, drill, chinolinyl, tetrahidrokinolinyl, and 4-azudrill, but is not limited.The heteroaril ring can be bonded to the pendant group in any environmental atoms that provide a stable structure, and one of the circles can be voluntarily replaced unless specified specified.In some embodiments, hetererir is replaced by 1, 2, 3, or four substituents.

[0057] When used in the spectral book, the term "heterocycloalkyl" represents a part -time, two -ring or polygan -style ring system, which is a bridge, controlled, or a spilling ring.At least one ring is non -aromatic, and the non -aromatic ring contains 1, 2, 3, or four hetero atoms selected independently of nitrogen, oxygen, and sulfur.The 5 members have 0 to 2 double bonds, and 6 and 7 members have 0 to 3 double bonds.Executive non -substituted heterocycloalkyl groups are carbon of 1 to 12 (for example, 1-11, 1 ~ 10, 1 ~ 9, 2 ~ 12, 2 ~ 10, 2 ~ 9).It is a thing.The term "heterocycloalkyl" also represents a complex ring compound with a cross -linked multi -ring structure, which has one or more carbon or hetero atoms cross -linked to two non -adjacent elements, such as a single ring,,, for example, a quinum crisinyl group.。The term "Heterocycloalkyl" is one or more of the above -mentioned component ring, carbon ring, complex aromas, complex circles, for example, aril ring, cyclohexan ring, cyclohexen ring, cyclo.Includes a two -ring, three -ring, and quadruple group, which is a pentan ring, cyclopentene ring, pyridine ring, or pyrrain ring.The example of the heterogloalkir group is pyloriginyl, piperiginyl, 1,2,3,4-tetrahidelokinolinyl, decahydrokinolinyl, dahythropyro ropilidine, and decahydronafridinyl.The heterocycloalkyl ring can be bonded to the pendant group in any environmental atoms that provide a stable structure, and one of the circles can be voluntarily replaced unless specified specified.

[0058] When used in the book, the term "hydroxy" represents the -OH group.

[0059] When used in the spectrum book, the term "hydroxyalkyl" represents the alkyl part replaced by one or more in one or more carbon atoms in one or more carbon atoms.

[0060] When used in the book, "heterogeneous body" means the deviation or compound of the present invention, an arbitrary heterogeneous body, a stereoscopic body, an atlop heterogeneous body, an entertainment or a stereomer.The compounds of the present invention can have one or more chiral center or double bonds, so it is a three -dimensional heterogeneous body, such as a double bonded anterometric body (that is, geometry e / z, or a giastreomer)., It is recognized that it exists as an Enancho (that is, (+) or (-), or Cis / Trans anometics). According to the present invention, the chemical structure described in the current detail, and therefore the present invention.The compounds are all corresponding three -dimensional heterogeneous body, that is, three -dimensional hom (eg, geometric pure, pure mirror image pure, or stereo pure, pure), and mirror image heterogeneous and stereoscopic mixture.It contains both (for example, lacemi compounds). In the compound of the present invention, the mirror image heterosexual and the stereoscopic mixture of the present invention are usually well -known, for example, chiral phase gas chromatography, chiral phase high -speed liquid chromatography, compound as chiral salt and salted form.By crystallization or crystallin in the chiral solvent of the compound, it can be decomposed into a component enachio or three -dimensional strap. ENCO Omar and a stereoscopic body are known as a known asymmetric synthesis method.It can also be obtained from the intensity or a mirror image opposite pure intermediate, reagent, and catalyst.

[0061] When used in the books, the term "linker" means that the compound obtained can achieve the IC50 of 2UM or less in the following embodiment and the Ras-Raf destruction assay protocol provided here.In the compound of equation I, it means the two -valid organic part that connects the part B to the partial W.

[0062] The purpose of this biochemical assay is to measure the ability to make the test compound easier to form a three -yuan complex between the nucleotide road RAS isoform and cyclophilin A, and the obtained three -yield complex., BRAF RBD It destroys bonds to the structure and inhibits the RAS signal transmission via the RAF effector.

[0063] In an assay buffer containing 25mm HEPES (pH7.3), 0.002%Tween20, 0.1%BSA, 100mm NACL and 5mm MGCL 2 , Cyclophilin A, HIS6-K-RASGMPPNP (or other RAS variants), and GST-BRAF RBD Combine with a 384 welle -season plate with 25 μm, 12.5 nm, and 50Nm end concentration, respectively.The compound is present in the platewell as a 10 -point 3x dilution series, which starts with the end of 30 μm.After 3 hours of incubation at 25 ° C, a mixture of anti-HIS EU-W1024 and anti-GST allopicocyanine was added to an assay samplewell at 10 nm and 50 nm, respectively, and reactions were incubated for 1.5 hours.Read the TR-FRET signal with a microplate leader (excitation 320nm, fluorescent 665 / 615nm).The compound that promotes the destruction of the RAS: RAF complex is identified as a decrease in the TR-FRET ratio to the DMSO controlled well.

[0064] In some embodiments, the linker contains a liner of 20 or less.In some embodiments, linkers include 15 or less direct chain atoms.In some embodiments, the linkers include 10 or less direct chain atoms.In some embodiments, the linker has a molecular weight of less than 500g / mol.In some embodiments, the linker has a molecular weight of less than 400g / mol.In some embodiments, the linker has a molecular weight of less than 300g / mol.In some embodiments, the linker has a molecular weight of less than 200 g / mol.In some embodiments, the linker has a molecular weight of less than 100g / mol.In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0065] When used in the current note, the "worthy organic part" is less than 500kDA.In some embodiments, the "worthy organic part" is less than 400kDA.In some embodiments, the "worthy organic part" is less than 300kDA.In some embodiments, the "worth organic part" is less than 200kDA.In some embodiments, the "worthy organic part" is less than 100kDA.In some embodiments, the "worth organic part" is less than 50kDA.In some embodiments, the "worth organic part" is less than 25kDA.In some embodiments, the "worth organic part" is less than 20KDA.In some embodiments, the "worth organic part" is less than 15KDA.In some embodiments, the "worth organic part" is less than 10KDA.In some embodiments, the "worthy organic part" is less than 1KDA.In some embodiments, the "worthy organic part" is less than 500g / mol.In some embodiments, the "worthy organic part" is in the range of 500g / mol to 500kDA.

[0066] When used in this specification, the term "three -dimensional heterogeneous body" is an arbitrary formula compound described in all possible, different organs, and structural forms (eg, the structural form (eg, the present book).), In particular, it means a stereoscopic homotonial form and structural structural structure, all gia stereomer, enachi oimer, or anetometer, or structural structural structure, in particular, is, in particular.Several compounds of the present invention can exist in different different types of heterogeneous forms, and all of the latter are included in the scope of the present invention.

[0067] When used in the current note, the term "sulfonyl" is -s (o) 2 -Call the base.

[0068] When used in the book, the term "thiocarbonyl" means -c (s)-group.

[0069] When used in the book, the term "vinyl ketone" means a group containing a carbonyl group directly binding to the carbon-carbon double bond.

[0070] When used in the book, the term "vinylsulphone" means a group containing a sulfonyl group directly bonded to the carbon-carbon double bond.

[0071] When used in the books, the term "inon" is a structure. [Formation] [In the formula, R is an arbitrary substituent suitable for chemicals described in the book.She represents a group containing.

[0072] The specific compounds described in this book are one of the various forms, such as salt format, protection form, professional drag form, ester form (eg, optical or structural heterogeneous body), and isotope.The artist who reads the present disclosure will understand that it can be provided or used.In some embodiments, reference to a specific compound may be associated with the specific form of the compound.In some embodiments, reference to a specific compound may be associated with the compound in any form.In some embodiments, for example, the preparation of a single three -dimensional straps of a compound is considered to be the form of the compound different from that of the lacemi mixture of the compound, and the specific salt of the compound is separate of the compound.The preparation that is considered to be different from the salt -shaped form and contains a double -bonded structural heterogeneous body ((Z) or (e)) is the other structural heterogeneous ((e) or other structural heterogeneous body (e) orIt is considered different from the one containing (Z)), and one or more atoms are different forms that are different from those that are present in reference preparations.It can be thought.

[0073] (Detailed explanation) Compound Ras inhibitors are provided in the current note.The approach described in this book is two -in -cell proteins that do not interact under synthetic ligand and normal physiological conditions: target proteins (eg, RAS), and the site that is widely expressed in cells.(Presentation protein) (for example, cyclophyllin A) requires the formation of a high -viney component complex.More specifically, in some embodiments, the RAS inhibitors described in this book are highly relative between RAS proteins and Cyclophilin A (Cypa), a wide range of sites, Sol Shas Caston.Includes a new binding pocket site d in RAS by driving the formation of a sex bird complex.Although it is not bound by the theory, the method in which the inhibitory effect on the RAS is affected by the compound and complex of the present invention is the interaction site between the RAS and the downstream effector molecule such as RAF.The present inventors believe that three -dimensional obstruction is formed, which is necessary to grow the carcinogenic signal.

[0074] Although it is not bound by the theory, the non -shared interaction between the compounds of the present invention between the RAS and the chapertonic protein (for example, cyclophyllin A) can contribute to the inhibition of RAS activity.doing.For example, the ability in which the compound of the invention forms a complex in which the compound of the invention forms a complex, for which the compound of the invention forms a compound of the invention, for which the compound of the invention forms a fan del's interaction, hydrophobic interaction, hydrophilic interaction, hydrophilic interaction, and hydrogen bond interaction.Can contribute to.Therefore, various RAS proteins can be inhibited by the compounds of the present invention (for example, K-RAS, N-Ras, H-Ras, and these variants in the position 12, 13, and 61.G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, and other items described in the Honesuki).

[0075] Therefore, we provide a compound having a structure of equation 00 or its pharmaceutically acceptable salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of the 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Allelen, or arbitrarily replaced 5 ~ 10.It is bonded to the carbon atom of the Hetero Allylene.] G is an arbitrarily replaced C 1 -C 4 Alkylene, arbitrarily replaced C 1 -C 4 Alkenylene, arbitrarily replaced C 1 -C 4 Heterocyulene, -c (o) o-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], -C (o) nh-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], C in arbitrarily replaced 1 -C 4 Heterocyulene or 3-8 heteralen, SWIP (switch I / P-loop) means an organic part that does not share to both the switch I binding pocket and the RAS protein P-loop residue 12 or 13 (for example, the current statement by reference.See Johnson et al., 292: 12981-12993 (2017), X 1 Is an arbitrarily replaced C 1 -C 2 Alkylene, NR, O, or S (O) n , X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 CH, CH 2 , Or N, Y 6 C (o), ch, ch 2 , Or N, R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 Alyl or hetereril of 5 to 10 members that are arbitrarily replaced R 1 And R 2 Forms a heterocycloalchill for 3 to 14 members that are arbitrarily replaced with the bonded atoms. R 2 Do not exist, hydrogen, arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 6 cycloalkyl, arbitrarily replaced 3 to 7 heterocycloalkyl, six arils of arbitrarily replaced, 5 or 6 Hetero.Alyl, R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7a And R 8a Is independent, hydrogen, halo, arbitrarily replaced c 1 -C 3 It is alkyl or combined with the carbon in which they bind, forming carbonyyl. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 10 Is hydrogen, halo, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, R 10a Is hydrogen or halo, and R 16 Is hydrogen or c 1 -C 3 Alkyl (for example, methyl).].In some embodiments, the obtained compounds can realize the IC50 of 2UM or less (for example, 1.5UM, 1UM, 500 nm, or 100 nm or less) in the Ras-Raf destruction assay protocol described in the present book.It is.

[0076] Therefore, we provide a compound having a structure of equation I or its pharmaceutically acceptable salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of the 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Allelen, or arbitrarily replaced 5 ~ 10.It is bonded to the carbon atom of the Hetero Allylene.] B does not exist, -ch (r) 9 )-or> C = CR 9 R 9’ [In the formula, carbon is -n (r) 11 C (o)-, 3 to 6 cycloalene, arbitrarily replaced, 3 to 6 heterocycloalene, six Alrain, or 5-6 members.It is bonded to the heteroseurelene carbonyl carbon.] G is an arbitrarily replaced C 1 -C 4 Alkylene, arbitrarily replaced C 1 -C 4 Alkenylene, arbitrarily replaced C 1 -C 4 Heterocyulene, -c (o) o-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], -C (o) nh-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], C in arbitrarily replaced 1 -C 4 Heterocyulene or 3-8 heteralen, L does not exist, or a linker, W is hydrogen, cyano, S (o) 2 R ', arbitrarily replaced amino, arbitrarily replaced amide, arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. X 1 Is an arbitrarily replaced C 1 -C 2 Alkylene, NR, O, or S (O) n , X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 CH, CH 2 , Or N, Y 6 C (o), ch, ch 2 , Or N, R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 Alyl or hetereril of 5 to 10 members that are arbitrarily replaced R 1 And R 2 Forms a heterocycloalchill for 3 to 14 members that are arbitrarily replaced with the bonded atoms. R 2 Do not exist, hydrogen, arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 6 cycloalkyl, arbitrarily replaced 3 to 7 heterocycloalkyl, six arils of arbitrarily replaced, 5 or 6 Hetero.Alyl, R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7a And R 8a Is independent, hydrogen, halo, arbitrarily replaced c 1 -C 3 It is alkyl or combined with the carbon in which they bind, forming carbonyyl. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Hydrogen, F, arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, arbitrarily replaced cycloalual kill, or heterocycloalkyl of 3 to 7 members that are arbitrarily replaced. R 9 And L forms a heterocycloalkyl for 3 to 14 members that are arbitrarily replaced with the atoms they bind. R 9’ Is hydrogen or arbitrarily replaced c 1 -C 6 Alkyl, R 10 Is hydrogen, halo, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, R 10a Is hydrogen or halo, R 11 Is hydrogen or c 1 -C 3 Alkyl, R 16 Is hydrogen or c 1 -C 3 Alkyl (for example, methyl).].

[0077] In some embodiments, the present disclosure features a structural IA compound or its pharmaceutical salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of the 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Allelen, or arbitrarily replaced 5 ~ 10.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-or> C = CR 9 R 9’ [In the formula, carbon is -n (r) 11 C (o)-, 3 to 6 cycloalene, arbitrarily replaced, 3 to 6 heterocycloalene, six Alrain, or 5-6 members.It is bonded to the heteroseurelene carbonyl carbon.] G is an arbitrarily replaced C 1 -C 4 Alkylene, arbitrarily replaced C 1 -C 4 Alkenylene, arbitrarily replaced C 1 -C 4 Heterocyulene, -c (o) o-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], -C (o) nh-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], C in arbitrarily replaced 1 -C 4 Heterocyulene or 3-8 heteralen, L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. X 1 Is an arbitrarily replaced C 1 -C 2 Alkylene, NR, O, or S (O) n , X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 CH, CH 2 , Or N, Y 6 C (o), ch, ch 2 , Or N, R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 Alyl or hetereril of 5 to 10 members that are arbitrarily replaced R 1 And R 2 Forms a heterocycloalchill for 3 to 14 members that are arbitrarily replaced with the bonded atoms. R 2 Do not exist, hydrogen, arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 6 cycloalkyl, arbitrarily replaced 3 to 7 heterocycloalkyl, six arils of arbitrarily replaced, 5 or 6 Hetero.Alyl, R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7a And R 8a Is independent, hydrogen, halo, arbitrarily replaced c 1 -C 3 It is alkyl or combined with the carbon in which they bind, forming carbonyyl. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, arbitrarily replaced cycloalual kill, or heterocycloalkyl of 3 to 7 members that are arbitrarily replaced. R 9 And L forms a heterocycloalkyl for 3 to 14 members that are arbitrarily replaced with the atoms they bind. R 9’ Is hydrogen or arbitrarily replaced c 1 -C 6 Alkyl, R 10 Is hydrogen, halo, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, R 10a Is hydrogen or halo, and R 11 Is hydrogen or c 1 -C 3 Alkyl.].

[0078] In some embodiments, the present disclosure features a structural IB compound or its pharmaceutically acceptable salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, carbon is -n (r) 11 C (o)-, 3 to 6 cycloalene, arbitrarily replaced, 3 to 6 heterocycloalene, six Alrain, or 5-6 members.It is bonded to the heteroseurelene carbonyl carbon.] G is an arbitrarily replaced C 1 -C 4 Alkylene, arbitrarily replaced C 1 -C 4 Alkenylene, arbitrarily replaced C 1 -C 4 Heterocyulene, -c (o) o-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], -C (o) nh-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], C in arbitrarily replaced 1 -C 4 Heterocyulene or 3-8 heteralen, L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. X 1 Is an arbitrarily replaced C 1 -C 2 Alkylene, NR, O, or S (O) n , X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 And y 6 Is independent, ch or n R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 Hydrogen, C in arbitrarily replaced 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, 3 to 6 cycloalkyl, arbitrarily replaced 3-7 heterocycloalkyl, 6 aril of arbitrarily replaced, 5 or 6 Hetero.Alill, R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced R 10 Hydrogen, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, and R 11 Is hydrogen or c 1 -C 3 Alkyl.].

[0079] In some embodiments of the compounds of the present invention, G is arbitrarily replaced. 1 -C 4 Heterocyane.

[0080] In some embodiments, the compounds of the present invention have the structure of the equation IC or their pharmaceutical salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, carbon is -n (r) 11 C (o)-, 3 to 6 cycloalene, arbitrarily replaced, 3 to 6 heterocycloalene, six Alrain, or 5-6 members.It is bonded to the heteroseurelene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y4 , And y 7 Is independent, C or N, Y 5 And y 6 Is independent, ch or n R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 Hydrogen, C in arbitrarily replaced 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, 3 to 6 cycloalkyl, arbitrarily replaced 3-7 heterocycloalkyl, 6 aril of arbitrarily replaced, 5 or 6 Hetero.Alyl R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced R 10 Hydrogen, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, and R 11 Is hydrogen or c 1 -C 3 Alkyl.].

[0081] In some embodiment of the compounds of the present invention, x 2 Is NH.In some embodiments, x 3 Is CH.

[0082] In some embodiment of the compounds of the present invention, R 11 Is hydrogen.In some embodiments, R 11 C 1 -C 3 Alkyl.In some embodiments, R 11 Is methyl.

[0083] In some embodiments, the compounds of the present invention have the structure of the equation ID or the pharmaceutically acceptable salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 And y 6 Is independent, ch or n R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 Hydrogen, C in arbitrarily replaced 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, 3 to 6 cycloalkyl, arbitrarily replaced 3-7 heterocycloalkyl, 6 aril of arbitrarily replaced, 5 or 6 Hetero.Alill, R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl, or heterocycloalchill of 3 to 7 members that are arbitrarily replaced. R 10 Hydrogen, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl.].

[0084] In some embodiment of the compounds of the present invention, x 1 Is an arbitrarily replaced C 1 -C 2 Alkylene.In some embodiments, x 1 Is methylene.In some embodiments, x 1 , C 1 -C 6 It is a methylene replaced by an alkyl group or halogen.In some embodiments, x 1 Is -ch (br )-.In some embodiments, x 1 -Ch (ch (ch) 3 ).

[0085] In some embodiment of the compounds of the present invention, R 3 Does not exist.

[0086] In some embodiment of the compounds of the present invention, R 4 Is hydrogen.

[0087] In some embodiment of the compounds of the present invention, R 5 Is hydrogen.In some embodiments, R 5 Is an arbitrarily replaced by halogen 1 -C 4 Alkyl.In some embodiments, R 5 Is methyl.

[0088] In some embodiment of the compounds of the present invention, y 4 Is C.In some embodiments, y 5 Is CH.In some embodiments, y 6 Is CH.In some embodiments, y 1 Is C.In some embodiments, y 2 Is C.In some embodiments, y 3 Is N.In some embodiments, y 7 Is C.

[0089] In some embodiments, the compounds of the present invention have the structure of the equation IE or their pharmaceutical salt: [Formation] [In the formula, A is -n (h or ch) 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 Hydrogen, C in arbitrarily replaced 1 -C 6 Alkyl, arbitrarily replaced C 2 -C6 Alkenyl, 3 to 6 cycloalkyl, arbitrarily replaced 3-7 heterocycloalkyl, 6 aril of arbitrarily replaced, 5 or 6 Hetero.Alill, R 3 Does not exist, or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl, or heterocycloalchill of 3 to 7 members that are arbitrarily replaced. R 10 Hydrogen, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl.].

[0090] In some embodiment of the compounds of the present invention, R 6 Is hydrogen.

[0091] In some embodiment of the compounds of the present invention, R 2 Hydrogen, cyano, arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced cycloalocyl, or heterocyroquill for 3 to 6 members arbitrarily replaced.In some embodiments, R 2 Is an arbitrarily replaced C, such as ethyl 1 -C 6 Alkyl.In some embodiments, R 2 Is fluoro C 1 -C 6 Alkyl, for example, -ch 2 Ch 2 F, -ch 2 Chf 2 , Or -ch 2 CF 3 It is.

[0092] In some embodiment of the compounds of the present invention, R 7 Is an arbitrarily replaced C 1 -C 3 Alkyl.In some embodiments, R 7 C 1 -C 3 Alkyl.

[0093] In some embodiment of the compounds of the present invention, R 8 Is an arbitrarily replaced C 1 -C 3 Alkyl.In some embodiments, R 8 Is C for methyl, etc. 1 -C 3 Alkyl.

[0094] In some embodiments, the compounds of the present invention have the structure of the equation IF or their pharmaceutical salt: [Formation] In the formula, A is an arbitrarily replaced cycloalen, 3 to 6 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced.It ’s a 5-6 heterearlen, B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, and R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, or 3 to 7 heterocyroquills for arbitrarily replaced.].

[0095] In some embodiment of the compounds of the present invention, R 1 Is a 5 to 10 hetererir.In some embodiments, R 1 Is a hetererir of the six areas of six members, or the six hetererils that have been arbitrarily replaced.

[0096] In some embodiment of the compounds of the present invention, R 1 teeth, [Formation] Or these three -dimensional straps.In some embodiments, R 1 teeth [Formation] Or its three -dimensional opposition.Depending on the embodiment, R 1 teeth, [Formation] It is.In some embodiments, R 1 teeth [Formation] Or its three -dimensional opposition.Depending on the embodiment, R 1 teeth, [Formation] It is.

[0097] In some embodiments, the compounds of the present invention have the structure of the equation IG or their pharmaceutical salt: [Formation] In the formula, A is an arbitrarily replaced cycloalen, 3 to 6 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced.It ’s a 5-6 heterearlen, B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced X e N, ch, or CR 17 , X f Is n or ch, R 12 Is an arbitrarily replaced C 1 -C 6 Alkyl or arbitrarily replaced C 1 -C 6 Heterocyl, and R 17 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 aryls or hetererirs of 5 to 10 members arbitrarily replaced.].

[0098] In some embodiment of the compounds of the present invention, x e Is n, x f Is CH.In some embodiments, x e Is CH, x f Is N.In some embodiments, x e CR 17 And X f Is N.

[0099] In some embodiment of the compounds of the present invention, R 12 Is an arbitrarily replaced C 1 -C 6 It is a heter alkill.In some embodiments, R 12 teeth, [Formation] It is.

[0100] In some embodiments, the compounds of the present invention have the structure of the equation IH or their pharmaceutical salt: [Formation] In the formula, A is an arbitrarily replaced cycloalen, 3 to 6 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced.It ’s a 5-6 heterearlen, B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced X e , CH, or CR 17 And, and R 17 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 aryls or hetererirs of 5 to 10 members arbitrarily replaced.].

[0101] In some embodiments, the compounds of the present invention have the structure of equation II or their pharmaceutical salt: [Formation] In the formula, A is an arbitrarily replaced cycloalen, 3 to 6 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced.It ’s a 5-6 heterearlen, B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, and R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, or 3 to 7 heterocyroquills for arbitrarily replaced.].

[0102] In some embodiments of the compounds of the present invention, A is an arbitrary Allylen of the six members.In some embodiments, A is a structure [Formation] [In the formula, R 13 Hydrogen, hydroxy, amino, cyano, arbitrarily replaced C 1 -C 6 Alkyl or arbitrarily replaced C 1 -C 6 It is a heter alkill.].In some embodiments, R 13 Is hydrogen.In some embodiments, R 13 Is a hydroxy.In some embodiments, A is an arbitrarily substituted 5 to 10 hetererlene.In some embodiment, A is [Formation] It is.In some embodiments, A is an arbitrarily substituted 5-6 hetererlenh.In some embodiment, A is [Formation] It is.In some embodiment, A is [Formation] It is.

[0103] In some embodiment of the compounds of the present invention, B is -chr 9 -Be.In some embodiments, R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl or cycloalkyl of 3 to 6 members that are arbitrarily replaced.In some embodiments, R 9 teeth, [Formation] It is.In some embodiments, R 9 teeth, [Formation] It is.In some embodiments, R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, or 3 to 7 heterocyroquills for arbitrarily replaced.

[0104] In some embodiments, B is an arbitrarily replaced Alrain.

[0105] In some embodiments, B is an Alrain of six members.In some embodiment, B is [Formation] It is.In some embodiments, B does not exist.

[0106] In some embodiment of the compounds of the present invention, R 7 Is methyl.

[0107] In some embodiment of the compounds of the present invention, R 8 Is methyl.

[0108] In some embodiment of the compounds of the present invention, R 16 Is hydrogen.

[0109] In some embodiments of the compounds of the present invention, the linker is the structure of the equation II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Equation II [In the formula, A 1 Is the bond between the linker and the B; a 2 Is a bond between W and the linker; b 1 , B 2 , B 3 , And B 4 Each is independent and is arbitrarily replaced. 1 -C 2 Alkylene, arbitrarily replaced C 1 -C 3 Heterocyulene, O, S, and NR N Selected from; r N Hydrogen, C in arbitrarily replaced 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 3 Cycloalkyl, arbitrarily replaced C 2-C4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, arbitrarily replaced heterocycloalchill, arbitrarily replaced aryl, or arbitrarily replaced. 1 -C 7 Heterocyl; c 1 And C 2 Selected from carbonyyl, thiocarbonyl, sulfonyl, or phosphoryl, each of which is independent; F, G, H, I, J, and K are independent, 0 or 1. 1 Is an arbitrarily replaced C 1 -C 10 Alkylene, arbitrarily replaced C 2 -C 10 Alkenylene, arbitrarily replaced C 2 -C 10 Alquinylene, 3 to 14 heterocycloalene, arbitrarily replaced, 5 to 10 hetererlene, 3 to 8 cycloalquils, arbitrarily replaced, 6 ~ 10.Arielen of the member, C, is an arbitrarily replaced C 2 -C 10 Polyethylene glycorene or C in arbitrarily replaced 1 -C 10 Heterocyulene or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h --- (b 3 ) i -(C 2 ) j -(B 4 ) k -A 2It is a chemical bond to bind to.].In some embodiments, the linker is non -ring.In some embodiments, the linker has the structure of the equation IIA: [Formation] [In the formula, x a Does not exist, or n, R 14 Is not existed, hydrogen or arbitrarily replaced c 1 -C 6 Alkyl or arbitrarily replaced C 1 -C 3 Cycloalkyl, and L 2 Does not exist, -c (o)-, --so 2 -, A arbitrarily replaced C 1 -C 4 Alkylene or C in arbitrarily replaced 1 -C 4 Heterocyane, x a , R 14 , Or L 2 At least one of them exists.].In some embodiments, linkers have the following structure: [Formation] In some embodiment, L is [Formation] It is.In some embodiment, L is [Formation] It is.In some embodiments, the linker is a ring group or a circular group.In some embodiments, the linker has the structure of the equation IIB: [Formation] [In the formula, O is 0 or 1, X b C (o) or so 2 , R 15 Is hydrogen or arbitrarily replaced c 1 -C 6 Alkyl, CY is an arbitrary 3 to 8 cycloalen, 3 to 8 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced 5 ~.10 Heteralen, and L 3 Does not exist, -c (o)-, --so 2 -, A arbitrarily replaced C 1 -C 4 Alkylene or arbitrarily replaced C 1 -C 4 Heterocyane.].In some embodiments, linkers have the following structure: [Formation] [Formation]

[0110] In some embodiments of the compounds of the present invention, W is an arbitrarily replaced amino, an arbitrarily replaced amino. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, arbitrarily replaced heterocycloalchill, 3 to 8 cycloalkills, or heteryl of 3 to 8 members.

[0111] In some embodiments of the compounds of the present invention, W is hydrogen.In some embodiments, W is an arbitrarily replaced amino.In some embodiments, W is -nhch 3 Or -n (ch 3 ) 2 It is.In some embodiments, W is an arbitrarily replaced C. 1 -C 4 Alcooxy.In some embodiments, W is a metoxy or isopro poxy.In some embodiments, W is an arbitrarily replaced C. 1 -C 4 Alkyl.In some embodiments, W is methyl, ethyl, isopropyl, tert-butyl, or benzyl.In some embodiments, W is an arbitrarily replaced amide.In some embodiment, W is [Formation] It is.In some embodiments, W is an arbitrarily replaced amide.In some embodiment, W is [Formation] It is.In some embodiments, W is an arbitrarily replaced C. 1 -C 4 It is a hydroxial kill.In some embodiment, W is [Formation] It is.In some embodiments, W is an arbitrarily replaced C. 1 -C 4 Amino alkyl.In some embodiment, W is [Formation] It is.In some embodiments, W is an arbitrarily replaced C. 1 -C 4 Hello alkyl.In some embodiment, W is [Formation] It is.In some embodiments, W is an arbitrarily replaced C. 1 -C 4 Guanidino Alkyl.In some embodiment, W is [Formation] It is.In some embodiments, W is C. 0 -C 4 Alkyl is a heterocyclo -alkyl of 3 to 11 members that are arbitrarily replaced.In some embodiment, W is [Formation] [Formation] [Formation] [Formation] [Formation] It is.In some embodiments, W is an arbitrarily replaced cycloalquill.In some embodiment, W is [Formation] It is.In some embodiments, W is an arbitrarily substituted 3 to 8 hetereril.In some embodiment, W is [Formation] It is.In some embodiments, W is an arbitrary 6 to 10 aryls (eg, phenyl, 4-hydroxy-phenyl, or 2,4-metoxy-phenyl).

[0112] In some embodiments, the compounds of the present invention are selected from Table 1 or their pharmaceutically acceptable salt or three -dimensional strap.In some embodiments, the compounds of the present invention are selected from Table 1 or their pharmaceutically acceptable salt or atlop straps.

[0113] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32] [Table 1-33] [Table 1-34] [Table 1-35] [Table 1-36] [Table 1-37] [Table 1-38] [Table 1-39] [Table 1-40] [Table 1-41] [Table 1-42] [Table 1-43] [Table 1-44] [Table 1-45] [Table 1-46] [Table 1-47] [Table 1-48] [Table 1-49] [Table 1-50] [Table 1-51] [Table 1-52] [Table 1-53] [Table 1-54] [Table 1-55] [Table 1-56] [Table 1-57] [Table 1-58] [Table 1-59] [Table 1-60] [Table 1-61] [Table 1-62] [Table 1-63] [Table 1-64] [Table 1-65] [Table 1-66] [Table 1-67] [Table 1-68] [Table 1-69] [Table 1-70] [Table 1-71] [Table 1-72] [Table 1-73] [Table 1-74] [Table 1-75] [Table 1-76] [Table 1-77] [Table 1-78] [Table 1-79] [Table 1-80] [Table 1-81] [Table 1-82] [Table 1-83] [Table 1-84] [Table 1-85] [Table 1-86] [Table 1-87] [Table 1-88] [Table 1-89] [Table 1-90] [Table 1-91] [Table 1-92] [Table 1-93] [Table 1-94] [Table 1-95] [Table 1-96] [Table 1-97] [Table 1-98] [Table 1-99] [Table 1-100] [Table 1-101] [Table 1-102] [Table 1-103] [Table 1-104] [Table 1-105] [Table 1-106] [Table 1-107] [Table 1-108] [Table 1-109] [Table 1-110] [Table 1-111] [Table 1-112] [Table 1-113] [Table 1-114] [Table 1-115] [Table 1-116] [Table 1-117] [Table 1-118] [Table 1-119] [Table 1-120] [Table 1-121] [Table 1-122] [Table 1-123] [Table 1-124] [Table 1-125] [Table 1-126] [Table 1-127] [Table 1-128] [Table 1-129] [Table 1-130] [Table 1-131] [Table 1-132] [Table 1-133] [Table 1-134] [Table 1-135] [Table 1-136] [Table 1-137] [Table 1-138] [Table 1-139] [Table 1-140] [Table 1-141] [Table 1-142] [Table 1-143] [Table 1-144] [Table 1-145] [Table 1-146] [Table 1-147] [Table 1-148] [Table 1-149] [Table 1-150] [Table 1-151] [Table 1-152] [Table 1-153] [Table 1-154] [Table 1-155] [Table 1-156] [Table 1-157] [Table 1-158] [Table 1-159] [Table 1-160] [Table 1-161] [Table 1-162] [Table 1-163] [Table 1-164] [Table 1-165] [Table 1-166] [Table 1-167] [Table 1-168] [Table 1-169] [Table 1-170]

[0114] It should be noted that some compounds indicate the bonds as flat or wedding.In some cases, the relative three -dimensional chemistry of the three -dimensional strap is measured.In some cases, absolute stereoscopic is measured.In some cases, a single embodiment number corresponds to a mixture of a three -dimensional object.All three -dimensional straps of the compounds of the table described above are considered by the present invention.In a specific embodiment, the atropemic object of the compound described above is considered.All compounds indicated in parentheses indicate that the compound is a Zia stereomer, and the absolute stereosomer of such a stereomer cannot be shown.

[0115] In some embodiments, the compounds of Table 2 or their pharmaceutical salt are provided.In some embodiments, the compounds of the present invention are selected from Table 2 or their pharmaceutically acceptable salt or atlop straps. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27] [Table 2-28] [Table 2-29] [Table 2-30] [Table 2-31] [Table 2-32] [Table 2-33] [Table 2-34] [Table 2-35] [Table 2-36]

[0116] It should be noted that some compounds indicate the bonds as flat or wedding.In some cases, the relative three -dimensional chemistry of the three -dimensional strap is measured.In some cases, absolute stereoscopic is measured.All three -dimensional straps of the compounds of the table described above are considered by the present invention.In a specific embodiment, the atropemic object of the compound described above is considered.

[0117] In some embodiments, the compounds of the present invention will act as a professional drug or, for example, a cell or a professional drug for administration to the required object.

[0118] In another embodiment, the present invention provides pharmaceutical compositions, including the compounds of the present invention or their pharmaceutically acceptable salt, and the pharmaceutically acceptable.

[0119] The treatment method of cancer in the subject that requires cancer treatment is the above -mentioned method of the compound of the present invention that is effective for treatment, or the pharmaceutical salt.We provide further methods, including what to do.Cancer can be, for example, pancreatic cancer, columnar cancer, non -small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid cancer, bone marrow -like syndrome, or plaquehehelnal cancer.In some embodiments, cancer includes Ras such as K-RAS G12C, K-RAS G12D, K-RAS G12V, K-RAS G12S, K-Ras G13C, K-Ras G13D, or K-RAS Q61L.Includes mutation.Other RAS mutations are described in this book.

[0120] The treatment method of RAS protein -related diseases in the subject that requires the treatment of RAS protein -related diseases is the above -mentioned method, or is acceptable for treatment, or its pharmacy.The above methods, including administration of salt, are further provided.

[0121] It is a method of inhibiting RAS proteins in cells, and further provides the above method, including the above method, including the above -mentioned cells in contact with the compounds of the effective amount of the present invention or their pharmaceutical salt.do.For example, RAS proteins are K-RAS G12C, K-RAS G12D, K-RAS G12V, K-RAS G12S, K-Ras G13C, K-Ras G13D, or K-RAS Q61L.Other RAS proteins are described in Honako.Cells include pancreatic cancer cells, colon celluloptical leukemia cells, acute myelinoma cells, polycopic myeloma cells, thyroid cancer cells, bone marrow -type syndrome cells, or small flat skin canceria.Can be cancer cells.The types of other cancers are described in this book.The cells may be Invibo or Invitro.

[0122] In the compounds of the present invention, a three -dimensional opposite body may show better inhibition than another three -dimensional opposite body.For example, while a certain atropemic body can be inhibited, the other atropometers cannot be indicated or at all indicated.

[0123] In some embodiments, the method or use described in this book further includes additional administration of additional anticancer treatment.In some embodiments, additional anticancer treatments include HER2 inhibitors, EGFR inhibitors, second RAS inhibitors, SHP2 inhibitors, SOS1 inhibitors, RAF inhibitors, MEK inhibitors, and ERK inhibitors., PI3K inhibitor, PTEN inhibitor, AKT inhibitor, Mtorc1 inhibitor, Braf inhibitor, PD-L1 inhibitor, PD-1 inhibitor, CDK4 / 6 inhibitor, or combination of these.In some embodiments, the additional anticancer treatment is SHP2 inhibitor.Other additional anticancer treatments are described in this book.

[0124] Synthetic method The compounds described in this book can be made from commercially available departure materials, or are synthesized using the known organic, inorganic, or enzyme processes.

[0125] The compounds of the present invention can be prepared in several methods known to organic synthesis art.For example, the compounds of the present invention can be synthesized using the following scheme, along with the methods shown in the following scheme, along with the method of knowledge in the field of organic synthetic chemistry, or the methods that are understood by the art.。These methods include the following scheme, but not limited.

[0126] The compounds in the current detailed text are prepared using the method of disclosing them in the present document, or in combination with the knowledge of the art, the method to be disclosed in the present document was prepared.The compounds in Table 2 can be prepared using the method of disclosing in the edible book, or in combination with the skills of the art, the method to be disclosed in the present book can be prepared.

[0127] Schem 1.General synthesis of large ring ester [Formation]

[0128] The general synthesis of the large ring ester is outlined to a scheme 1.The appropriately replaced alyl indoor intermediate (1) is a protected 3- (5-bromo-2-iodo-1H-indole-3-Il) -2,2-2,2-Dimethyl propane-1-all and appropriatelyIt can be prepared in three steps, including palladium brokered coupling, alkylation, and protection reaction starting from replaced boronic acid.

[0129] Methyl-Amino-Hexahydropilidadine-3-Carboxylate-Esther (2), a boronization of protection, an iridium catalyst, and a methyl (S) -Hexahydropyridazine-3-Calvoxilate 3 steps.Can be prepared in.

[0130] Methyl -L-barrinate and protected (s) -3-carboxylic acid, then protected, coupling with appropriately substituted carboxylic acid, and appropriate by hydrolyzing.Acetylpyrridine-3-carbonyl-n-methyl-baline (4) replaced with can be produced.

[0131] In the existence of a PD catalyst, the finals of the coupling of methyl-amino-hexahydropyridadin-3-carboxylate-boronicate (2) and intermediate (1), followed by hydrolysis and macractone.A large ring ester is produced, and a large ring intermediate (5) that is appropriately protected.Large ring product is obtained by the coupling by protection and appropriately replaced acetylpyrridine-3-carbonyl-n-methyl-baline (4).In order to create the final compound, an additional escape or sensual basis process is required.For example, the artist uses the method listed in the Examinated Examples of the present Dosho, so that the large ring ester, the desired-B-L-W group of the formula (I) (I), the desired formula of the formula (I) [Equation, B, L, and WIs as defined in the current thin book.] Will be introduced.

[0132] Scheme 2. General synthesis of replacement of large ring ester [Formation]

[0133] Alternatively, the large ring ester can be prepared as described in the scheme 2.The appropriately protected bromo-Indillill (6) can be coupled with the Eter (3) boronate (3) in the presence of a PD catalyst, followed by iodine, protection, and ester hydrolysis.After coupling with methyl (S) -Hexahydropilidadine-3-carboxylate, it can be hydrolyzed and macrolacton to obtain an iodine intermediate (7).Under the existence of a PD catalyst, a completely protected large ring compound (5) can be obtained by coupling with the appropriately replaced boronicate ester and alkylating.In order to create the final compound, an additional escape or sensual basis process is required.For example, the artist uses the method listed in the Examinated Examples of the present Dosho, so that the large ring ester, the desired-B-L-W group of the formula (I) (I), the desired formula of the formula (I) [Equation, B, L, and WIs as defined in the current thin book.] Will be introduced.

[0134] Schem 3.General synthesis of large ring ester [Formation]

[0135] Alternatively, a large ring product can be obtained by removing a completely protected large ring compound (5) and coupling and protecting the appropriately replaced coupling partner.In order to create the final compound, an additional escape or sensual basis process is required.For example, the artist uses the method listed in the Examinated Examples of the present Dosho, so that the large ring ester, the desired-B-L-W group of the formula (I) (I), the desired formula of the formula (I) [Equation, B, L, and WIs as defined in the current thin book.] Will be introduced.

[0136] Schem 4.General synthesis of large ring ester [Formation]

[0137] The general synthesis of the substitute for large ring ester is abbreviated as scheme 4.Appropriately replaced Indronalille Boronate (8) is a protected 3- (5-bromo-2-iodo-1H-Indole-3-Il) -2,2-Dimethylopan-1-all and appropriate.It can be prepared in four steps, including palladium brokeric coupling, alkylation, protection, and palladium, which starts with boronic acid replaced with.

[0138] (S) -2-amino-3- (4-bromochiazol-2-Il) Methyl (S) -Hexahydropyridadin-3-Coulboxylate of Propropic acid (9), methyl-amino-amino-3- (4-Bromochiazol-2-Il) Propoil) Hexhadropyridazine-3-carboxilate (10) can be prepared.

[0139] Methyl-amino-3- (4-bromochiazol-2-Il) propanil in the existence of a PD catalyst) Hexahydropyridadin-3-carboxylate (10) and appropriately replaced Indolil boronate (8)), Followed by a hydrolyzed and macrolactonization process, and a final large ring ester (11) is formed.A large ring product can be obtained by protecting and appropriately replaced carboxylic acid (or other coupling partner) or a coupling with an intermediate 4.In order to produce the final compound 13 or 14, an additional protection or a sensual basis process may be required.

[0140] Furthermore, the compounds of the present disclosure can be synthesized using the method described in the following embodiment, along with the known method of synthesis in the technical field of synthetic organic chemistry, or the methods described in the following examples, along with the variations that are understood by the art.。These methods include the method described in the following embodiment, but not limited.For example, the artist uses the method listed in the Examinated Examples of the present Dosho, so that the large ring ester, the desired-B-L-W group of the formula (I) (I), the desired formula of the formula (I) [Equation, B, L, and WIs as defined in the current thin book.] Will be introduced.

[0141] Pharmaceutical composition and usage Pharmaceutical composition and administration method The compounds related to the present invention are RAS inhibitors and are useful for cancer treatment.Therefore, one embodiment of the present invention is the compound of the present invention or the pharmaceutical composition containing a pharmaceutically acceptable salt, and the pharmaceutical compound, and the compound of the present invention.Provides a method of preparing such a composition.

[0142] When used in the present invention, the term "pharmaceutical composition" means the compounds of the present invention, which are formulated with the pharmaceutically acceptable re -format, or their pharmaceutical salt.do.

[0143] In some embodiments, the compounds are in pharmaceutical compositions with a statistically significant treatment regimen, which provides a prescribed therapeutic effect when administered to a relevant group.exist.In some embodiments, pharmaceutical compositions include oral administration, for example, drinks (aqueous solution or non -aqueous solution or suspension), tablets, for example, cheeks, cheeks, tongue, and body absorption.Paste for applying to pills, powder, granules, and tongue; for example, a sterilized solution or suspension, or a sustained release of the muscle, intravenous, or dignified injection, for example, non -oral injection.Administration; for example, local application as a spray applied to cream, ointment, or inoperable release agent, or as a spray applied to the skin, lungs, or oral cavity;Inside the eye; perthalmol; or a nostrils, lungs, and other mucous films can be specially made for a solid or liquid form.

[0144] When used in the spectral book, the "pharmaceutically acceptable enrolled agent" is an arbitrary component that has a toxic and non -inflammatory properties within the subject (for example, a suspension of a active compound.It means dissolved behikuru).Typical, for example, anti -cohesis, anti -oxidant, binding agent, coating agent, compression agent, collapsed agent, dye (coloring agent), skin softening agent, emulsifier, filler (deception agent)., Collectant or coating agent, fragrance, fragrance, slapstick (fluid improvement agent), lubricant, preservatives, printing ink, adsorption, suspension agent or dispersion, sweeteners, or hydrate water.。The re -format is an arbitrarily replaced hidroxyl lune (BHT), calcium carbonate, calcium phosphate (two basic), calcium stearate, crosscal melody, cross -linked polyvinyl pyrrolidon, citrusic acid, crospovidon, castine, ethylicular loueseGelatin, arbitrarily replaced hydroxyl propylcellulose, arbitrarily replaced hydroxyl propylemethylcellulose, lactose, magnesium stearate, Multitol, methionine, methionine, methicellulose, methylpara louose, porivi -lilicol, polyethyl lycol, polyethyl lycall, polyethylpalricolDempin, propepyl paraben, palmitic acid, palmitic acid, serac, sodium sodium carboximethylulose, sodium citrate, sodium glycolate, sorbitol, starline acid, stearic acid, scroose, tark, vitamin A, bitamin, Vitamin E, Vitamin C, and Xylitol are not limited to these.The art of the art is familiar with various agents and materials that are useful as a levy agent.Please refer to Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients.chicago, Pharmaceutical Pres, 2005.In some embodiments, compositions include at least two different pharmacology.

[0145] The compound described in this book is provided or used in a salt form, for example, a pharmaceutically acceptable salt form, unless it is explicitly described or not.be able to.When used in this book, the term "pharmaceutically acceptable salt" is a human and a human and a human without having to cause excessive toxicity, irritation, allergic response within the normal range of reasonable medical judgment.It is suitable for using and using it with other animal tissue, and it means these salt in the main book, which is a rational profit / risk ratio.Pharmaceutically acceptable salt is well known in the technical field.It is described in -vch, 2008.Salt can be prepared separately by IN Situ during the final and purification of the compound described in the present book, or by reacting a free base base with a suitable organic acid.

[0146] The compound of the present invention can have an ionic group so that it can be prepared as a pharmaceutically acceptable salt.These salt can be an acid -added salt associated with inorganic or organic acids, or in the case of an acidic form of the compound of the present invention, it can be prepared from an inorganic or organic base.In some embodiments, the compound is prepared or used as a pharmaceutical salt prepared as a pharmaceutically acceptable acid or base.To form hydrochloric acid, sulfate, hydrocarate, acetic acid, lactic acid, lactic acid, or tartaric acid, and basic salt, and forecasting basic salt, caffeinated hydroxide, ammonium hydroxide, caffeine., Awarely acceptable acids and bases, such as various amines, are well known in the technical field.Appropriate salt preparation methods are fully established in the technical field.

[0147] Typically acidated salt, acetate, agipination, algine, ascorbic acid, asparagin, pencolagine, benzenzulfonate, hydroglite, heavy sulfate, borate, dotted, and dumpling., Campasulhonate, Citric acid, Cyclopen tantion propionate, zigurconate, dodecyl sulfate, ethanulfonate, glucohepton acid, gurcoheptonate, glyceroline acid, glycerine acid, hemptanate, hematate, hexan.Hydroxyl, hydrogenatite, hydrogenatite, 2- (arbitrarily replaced) hydroxyl-ethaneulphonate, lactovion acid, lactic acid, lauril sulfate, apple, apple.Acate, maleic acid, marronate, methane sulfonate, 2-naphtalentzulphonate, nicotinate, nitrate, nitrate, oleic acid, oxaltanic, oxaline, palmitinate, palmitic acid, pectinate, excess.Sulfate, 3-phenylpionic acid, phenyltopionate, phenylanate, piclinate, pivarate, pro pionate, stearate, stearate, stearate, sulfate, sulfate, tapic acid, torgenianate, toluence sulfonate, and wandercan.It includes acids and Yoshicate acid.Typical alkali or alkali earth metal salt include sodium, lithium, potassium, calcium, magnesium, etc.Includes dimethylamine, trimethylamine, triethylamine, ethylamine, etc., but not limited to these).

[0148] When used in the present document, the term "target" means any element in the animal world.In some embodiments, "target" means human at any growth stage.In some embodiments, "target" means human patient.In some embodiments, "target" means non -hit animal.In some embodiments, non -hit animals are mammals (eg, gaps, mouse, rats, rabbits, monosals, dogs, cats, cats, cows, pigs).In some embodiments, mammals, birds, reptiles, amphibians, fish, or insects are not limited.In some embodiments, the target can be transgenic animals, genetically modified animals, or clones.

[0149] When used in the spectrum book, the term "dosage form" means the physically separate unit of the compound (eg, the compound of the present invention) for administration to the target.Each unit contains a predetermined compound.In some embodiments, this amount follows the administration regimen that has been measured to be correlated with the desired or useful outcome when administered to a relevant group (that is, the treatment and administration regimen.It is an appropriate unit dose (or all the strokes) for administration.The artist understands that the total amount of treatment compositions or compounds administered to specific objects may be determined by one or more attending physicians and may be accompanied by multiple dosage forms.

[0150] When used in the books, the term "administration regimen" means the unity of the unit dose (usually twice or more times) that is usually separated in the period, which is usually separated.In some embodiments, the provided therapeutic compound (eg, the compound of the present invention) has a recommended administration of the recommended administration, which can have one or more doses.In some embodiments, the administration regimen contains multiple doses, each is separated into each other in the same length time, and in some embodiments, the administration regimen is multiple doses and individual doses.Divide doses include at least two different time periods.In some embodiments, all doses in the administered regimen are the same unit dose.In some embodiments, the different doses in the administered regimen are different.In some embodiments, the administration regimen includes the first dose in the first dose, followed by a further amount of one or more in the second dose different from the first dose.In some embodiments, the administration regimen includes the first dose in the first dose, followed by a further dose in the same dose as the first dose.In some embodiments, the administration regimen is correlated with the desired or beneficial outcomes (that is, the treatment regimen) when administered in a relevant group.

[0151] "Treatment regimen" means a administration regimen correlated with the desired or beneficial outcomes that spans related groups.

[0152] The term "treatment" (in addition, "treatment" or "treatment") is specified in the most broad sense of a specific disease, disability or medical condition, partially or completely remission, alleviating, and inhibiting.Partially or completely delayed the disease, disability or medical condition, a specific disease, disability or severity of the condition, or a specific disability, disability, or one or more.It means any administration of a substance (eg, compound of the present invention) that partially or completely reduces the occurrence of symptoms, characteristics, or causes.In some embodiments, such treatments can be administered to the subjects that do not show any signs of related diseases, disabilities or disability, or only the initial signs of disability, or initial symptoms.In alternatives, in some embodiments, such treatments can be administered to the treatment of related diseases, disabilities, or one or more of the condition of the condition.。In some embodiments, treatment may be diagnosed as having a relevant disease, disability or medical condition.In some embodiments, treatments are known to have one or more sensitivity factors that are statistically correlated with increased risk of relevant diseases, disabilities or medical conditions.good.

[0153] The term "effective amount for treatment" is a treatment for treatment, disability, disability or medical condition, in accordance with the disease, disability or medical condition, or when administered to a group where the disease, disability or medical condition is suspected.It means enough amount to do.In some embodiments, the amount effective for treatment is to reduce the occurrence or seriousness of one or more symptoms of disease, disability, or medical condition, or the start of one or more symptoms of disease, disability or medical condition.It is the amount to be delayed.The artist will understand that the term "effective for treatment" does not actually need to achieve the success of treatment with a particular individual.Rather, the amount effective for the treatment can be the amount that provides a specific pharmaceutical response in a significant number of targets when administered to the subject that requires such treatment.It is specifically understood that specific objects can actually be "inappropriate" for the "amount effective for treatment".In some embodiments, reference to the amount effective for treatment includes one or more specific tissues (eg, an organization affected by diseases, disability or medical condition), or fluids (for example, blood, saliva, serum, and so on.It can be referred to the amount measured by sweat, tears, urine).In some embodiments, the artist will understand that the amount effective for treatment can be made or administered in a single dose.In some embodiments, the amount effective for treatment can be made or administered by multiple doses, for example, as part of the administered regimen.

[0154] In order to be used as a treatment for the subject, the compound of the present invention, or its pharmaceutical salt, can be made into a pharmaceutical or veterinary composition.The method of treated, the desired treatment, and the desired treatment, for example, the compounds, or the hydrogenous salt, according to the prevention, prevention, or treatment method, match these parameters.It is prepared by.Remington: The Science and Practice of Pharmacy, 21 st It is incorporated in.

[0155] The compositions can be prepared according to the conventional mixture, granuling, or coating method, and this drug composition is about 0.1%to about 99%, about 5%to about 90%, or about 1%.It can contain a compound of about 20%(weight%or volume%) of the present invention, or a pharmaceutically acceptable salt.In some embodiments, the compounds described in the present book, or their pharmaceutical salt, are in total, 1 to 95%of the total weight of pharmaceutical compositions.Can do.

[0156] The compositions are in the joints, oral, non -oral (eg, veins, muscles), rectum, skin, subcutaneous, local, metal, nostrils, vaginal cavity, in the urethral.It can be provided in a fixing form that is suitable for direct contact with the dura, ears, or intraocular administration, or injecting, inhalation, or inhalation, or direct contact with the nose, urinary reproductive or gaps.Thus, pharmaceutical composition, for example, tablets, capsules, pharmaceuticals, powder, granules, suspensions, emulsions, solutions, hydrogel, gel, paste, cream, plastic, swash, penetration device, suppositories, enema.It can be a prepared material that is suitable for agent, injection solution, implant, spray, ion swimming delivery, or an air zole.The composition can be prepared according to the conventional pharmaceutical.

[0157] When used in the spectrum book, the term "administration" means the administration of the composition (for example, a compound, or a compound described in the book) to the target or system.The administration to an animal target (eg, human) may be due to any appropriate route.For example, in some embodiments, administration includes bronchi (including bronchial drip), cheeks, intestinals, intramutical (Interdermal), arterial, inside the skin, inside the gest, in the muscles, nasal, abdominal cavity.Inside, inside, intravenous, ventricular, mucous membranes, nasal, oral, rectum, subcutaneous, undercut, in the inside of the trachea (including internal infusions), inside the vagina, or in the vitreous.Can do.

[0158] The preparation can be prepared in a system suitable for general administration, local or local administration.It can be designed for injections (for example, in the muscles, in the veins, or subcutaneous injection) as a general formulation for general body, or it can be prepared for percutaneous, mucous membranes, or oral administration.。Preparations generally include diluted agents, and in some cases, injubant, buffer, preservatives, etc.The compounds, or their pharmaceutical salt, can also be administered in a liposom composition or as a micro -malment.

[0159] For injections, the formulation can be prepared as a solution or suspension, or as a solid form that is suitable for solution or suspension in the liquid before injection, or as an emulsion.Familiarly, for example, water, saline, dextrose, and glycerol are listed.Such a composition can also contain a certain amount of toxic auxiliary substances (eg, a wet agent or emulsifier), a pH buffer, for example, sodium acetate and sorvitan.

[0160] Various, pharmaceutical release systems are also devised.For example, please refer to US Patent No. 5,624,677.

[0161] As for the general administration, relatively non -invasive methods such as suppositories, percutaneous mounting agents, transcermilant delivery, and nasal administration can also be listed.Oral administration is also preferable to the compounds of the present invention, or those salt that are pharmaceutically acceptable.Familiar forms include syrup, capsules, and tablets, as understood in the technical field.

[0162] The compounds described in the present book, or their pharmaceutically acceptable salt, can be made in various ways in the technical field.For example, the first and second agents of the combined therapy can be combined or separately made.The other modalities of the combined therapy are described in the head book.

[0163] The agent that has been made individually or individually can be packaged as a kit.Examples of non -limited examples include kits containing two pills, pills and powder, liquids in vials, and two local creams, but not limited.The kit can contain any component that assists the target, such as a vial for reconstructing the powder form, a syringe for injection, a customized IV delivery system, and an inhalor.In addition, the unit quantity kit can contain a manual for preparing or administration of the composition.The kit is for specific targets for specific units for a certain target, (as a certain concentration or as the treatment progresses, or the effectiveness of the salted salt that is tolerated by the pharmaceutical)It may be manufactured multiple times, or the kit may contain a multi -turn dose (bulk packaging) suitable for administration to multiple objects.The components of the kit can be assembled in cartons, blister packs, bottles, tubes, etc.

[0164] The compound for oral use contains a tablet containing active ingredients (multiple) in a mixture with a pharmaceutically acceptable toxic thrust.These enrollment agents, for example, in -activated diluted agents or fillers, (for example, squares, sorbitol, sugar, sugar, mannitol, microtite cellulose, potato modern, calcium carbonated carbonate, sodium chloride, lactose, calcium sulfate, calcium sulfate., Or sodium phosphate); granate and collapse (for example, a starter derivative containing microtrous cellulose, starch containing a potato modernun, crosscar melody natrium, algin acid, or arginic acid);, Glucose, sorbitol, acacia, arginic acid, sodium arginate, algin acid, gelatin, starch, starch dick, microtite cellulose, carboxylic cellulose, carboxylic cellulose sellrose, methyl cellulose, pepper cellulose, pepper cellulose, エ セ セ セ セ 酸 酸 、 、 任 任 任 任 任 任 任 任 任 任 任 任 任 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、Or maybe a polyethylene glycol); and a smooth agent, a slide, and an anti -coating (for example, magnesium stearate, stearate zinc, stearic acid, silica, hardened vegetable oil, or tark).Other pharmaceutically acceptable enforced agents may be colored agents, flavoring agents, plasticizers, moisturizers, and buffers.

[0165] Two or more compounds can be mixed or divided in tablets, capsules, or other beichules.In one example, the first compound is contained inside the tablet, the second compound is on the outside, and the substantive part of the second compound is released before the first compound is released.

[0166] The formula for oral use can be provided as a chewing tablet, or the active ingredient is mixed with an inactive solid diluted agent (for example, barracoden, lactos, microt crystal cellulose, calcium carbonate, calcium phosphate, or kaolin).Gelatin capsules are also presented as gelatin capsules, or as water or oil culture, for example, peanut oil, fluid paraffin, or soft gelatin capsules that can be mixed with olive oil.Powder, granules, and pellets can be prepared using the above -mentioned components under the tablet and capsule in a conventional method using a mixer, a flowing floor device, or a spray drying device.

[0167] The dissolving or diffusion control and release can be realized by incorporating the compound tablets, capsules, pellets, or granular formation appropriate coats, or by incorporating compounds or their pharmaceutical salt into the appropriate matrix.。Sustained release coating includes the coating substances described above, or, for example, cerack, beeswax, glycowax, glycawax, culuna bowx, stearyl alcohol, monostyline acid glycerl, parmit stearlin, parmit stearlin, ethyl cellulose, acrylic.Resin, DL-polyac acid, cellulose acetate, cellulose, polyvinyl chloride, vinyl, polyacetate, vinyl pyrrolidon, polyethylene, polymetralate, methylmetaclate, 2- (arbitrarily replaced) Hydroxyl Metacleate, Metacrate Hydrogel, 1,3-ButilenIt can contain one or more glycol, ethylene glycol metacrate, or polyethylene glycol.Sustained release matrix preparations, for example, as matrix materials, for example, hydrate methylcellulose, carnauva wax and stearyl alcohol, carbo pole 934, silicone, glycerlic acid, methyl acrylate, metallic acid, polyethylene, polyethylene, polyethylene, polyethylene.Alternatively, a halogen -conated full orcocarbon can also be listed.

[0168] The compounds of the present invention, or their pharmaceutically acceptable salt, and the liquid forms that can be incorporated for administration by oral, are an aqueous solution, a suitable flavored syrup, aqueous or oil -based suspension.In addition, cotton oil, sesame oil, coconut oil, or peanut oils such as peanut oils, such as peanut oils, as well as ericyl agents and similar pharmaceutical beichules.

[0169] Generally, when administered to humans, the compounds of the present invention, or any of the pharmaceutically acceptable salt, may be determined by the skill of the compound and can be determined promptly by the art.For example, about 0.001 mg ~ about 2000 mg / day, about 1 mg ~ about 1000 mg / day, about 5mg ~ about 500 mg / day, about 100 mg ~ about 1500 mg / day, about 500 mg ~ about 1500 mg / day, about 500 mg ~ about 2000 mg / Sunday or any scope variable may be possible.

[0170] In some embodiments, pharmaceutical compositions can further contain additional compounds with antipultural activity.Depending on the method of administration, the compounds, or their pharmaceutically acceptable salt, are made into a suitable composition that enables easy delivery.Each compound of combined therapy, or its pharmaceutically acceptable salt, can be made in various ways in the technical field.For example, the first and second agents of the combined therapy can be combined or separately made.Instead, the first and second agents are prepared together for simultaneous administration of the drug or almost simultaneous administration.

[0171] The compounds and pharmaceutical compositions of the present invention can be made and used by combined therapy, that is, at the same time as one or more treatments or medical operations of compounds and pharmaceutical compositions.It can be understood that or that it can be made or administered after these.In a specific combination of a treatment method (therapeutic or procedure) that uses a combined regimen, take into account the desired treatment or procedure, and the desired treatment effects that are realized.In addition, it is understood that the treatment used can achieve the desired effect on the same disease, or have different effects (for example, control of all adverse effects).

[0172] As described in this book, the administration of each drug in combined therapy can be independent, can be once to four times a day from one day to one year, and in the life of the target.It may be.Chronic long -term administration may be shown.

[0173] how to use In some embodiments, the present invention discloses the treatment method of disease or disability, which is characterized by the ectopic RAS activity caused by the RAS mutant.In some embodiments, the disease or disability is cancer.

[0174] Therefore, it is a method of treating cancer in the subject that requires cancer treatment.The above method is also provided, including the administration of such a compound or a pharmaceutical composition containing such a compound or salt.In some embodiments, cancer includes colon rectum cancer, non -small cell lung cancer, small cell lung cancer, pancreatic cancer, oh sinatopsis, acute myeloma leukemia, small intestinal cancer, germ cell carcinoma, cervical carcinoma.Cancer, unknown nuclear -powered cancer, uterine body cancer, esophageal cancer, GI nerve endocrine cancer, ovarian cancer, sexual caterpillar tumor cancer, hepatical cancer, or bladder cancer.In some embodiments, cancer is a pemalid cancer, an endometrium cancer, or a black tumor.It is a treatment method of RAS protein -related diseases in the subject that requires the treatment of RAS protein -related diseases, and the above method is a compound of the present invention that is effective for treatment or its pharmaceutical.The above methods are also provided, including the administration of salt or pharmaceutical compositions containing such compounds or salt.

[0175] In some embodiments, for example, lung cancer, prostate, how to provide the compounds of the present invention, those that are pharmaceutically acceptable, such compounds or salt compositions, and how to provide them in this book.It can be used to treat a wide variety of cancers, including tumors such as cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer.More specifically, as a compound or its salt, such a compound or a pharmaceutical composition containing it, and a cancer that can be treated by the method of the present invention, it is a star -like cell, milk, cervical, colon rectum, uterus.Tumor species such as body, esophagus, stomach, head and neck, hepatocytes, lab, lungs, pharynx, ovaries, prostate, and thyroid cancer and sarcoma are not limited.For example, for other cancers, the following are listed: Heart, for example, non -epithelial malignant tumor (vascular sarcoma, fibrobarth, ridal crestedose, liposarcoma), mucosoma, ridal crop fibroids, fibroma, lipoma, and malformatoma; Lung, for example, bronchogenic cancer (squamous cells, unrealized small cells, non -differentiated cells, adenocarcinoma), alveolar (bronchi), bronchodema, non -epithelium malignant tumor, lymphoma, cartilage misfire,Makuroma; Gastrointestinal tract, for example, esophagus (flat cell carcinoma, adenocarrosis, smooth fibroids, lymphoma), stomach (epithelial malignant tumor, lymphoma, smooth fibroids), pancreas (pancreatic cancer, pancreatic celloma, glucagon -produced tumor, gaslin production, gaslin production.Tumor, cultinoid tumor, VIP producing tumor), small intestine (adenocarcinoma, lymphoma, cartinoidal, caposaroma, smooth fibroidoma, vasculema, lipema, neural fibroids, fibroids), large intestine (gland cancer, tube glutoma, and choral glutoma., Malfunction, smooth fibroid);); Urinary reproductive organs, for example, kidney (adenocarcinoma, virums tumor, (renal budy celloma), lymphoma, leukemia), bladder and urethral (squamous hypothelial cancer, migrational cancer, adenocarcinoma), prostate (adenocarcinoma, non -end skin.Malignant tumor), testicles (ventilatoma, malformedoma, embryos, malformed cancer, cherrinatoma, non -epithelial malignant tumor, interstitial cell carcinoma, fibroma, fibroidoma, gland tumor, lipoma); Liver, for example, liver cancer (hepatocellular cancer), bile duct cancer, hepatoprosis, blood vessel sarcoma, hepatocelicoma, vascularoma; Biliary tracts, for example, gallbladder cancer, expansion large cancer, bile duct cancer; Bone, for example, bone, fibrosarcoma, malignant fibrobial spheres, cartial sarcoma, ugly lymphoma, malignant lymphoma (netarcoma), multiple hereloma, malignant giant cell tumor index, bone.Osteochronfroma (osteochronFroma), benign cartilage tumor, cartilage sperm, cartilage mucus fibrooma, bone bone tumor, and giant cell tumor; Nerve system, for example, skulls (osteoma, hemangioma, granuloma, yellowoma, deformed bone), mening (meningoma, meningosarcoma), brain cells (star cells), brain (star cells).Temporary, cordo -bud, nervousoma, tumor, embryosia (pine glue), polygamic gluims, ultra -rash, neuralgia, retinal gluins, congenital tumors), spinal cord.Neuromyoma, nerve fibromy I type, meningema, nervousoma, non -epithelial malignant tumor); Gynecology, for example, uterus (endometrial cancer, uterine cancer, uterine endometrial cancer), cervical (cervical cancer, pre-tumor), cervical cervical (ovarian) (ovarian cancer).Serusic cystic gland carcinoma, mucous cystic gland cancer, non-classified cancer), granular film-cell cell tumor, Certoli lilic cell tumor, undifferentated embryo cells, malicious deformation), ventilation (flat skin cancer, epithelium, epidermis.In internal cancer, adenocarcinoma, fibroma, black tumor), vagina (cell carcinoma, squamous hypothelial cancer, grape sarcoma (fetal hydronnel), egg tube (epithelial malignant tumor); Hematology, for example, blood (acute leukemia (acute and chronic), acute lymph bud leukemia, chronic lymphocyte leukemia, bone marrow proliferation disease, multiple bone marrow syndrome), hosikin disease, non -bone -like syndrome).Hodgkin lymphoma (malignant lymphoma); Skin, for example, malignant blacken, basal cell carcinoma, squamous hematocarcinoma, caposarcoma, mole -formated nevus, lipoma, hemangioma, skin ray fibroids, keloids, psoriasis; Adrenal glands, for example, neuroblastoma.

[0176] In some embodiments, the RAS protein is a wild (RAS) WT )Therefore, in some embodiments, the compounds of the present invention are Ras. WT (For example, K-RAS WT , H-RAS WT Or N-RAS WT ) Used in the treatment method of patients with cancer containing cancer.In some embodiments, RAS proteins are RAS amplification (eg, K-RAS amp )Therefore, in some embodiments, the compounds of the present invention are Ras. amp (K-RAS amp , H-RAS amp Or N-RAS amp ) Used in the treatment method of patients with cancer containing cancer.In some embodiments, cancer includes RAS mutations such as RAS mutations described in the present book.In some embodiments, mutations are selected from the following: (a) K-Ras mutant: The following K-RAS variants: G12D, G12V, G12D, G13D, G12A, Q61H, Q61H, G12H, G13C, Q61L, Q61L, Q61L, K117NV, Q61K, L19I, A59T, A59T, A146P, G13R, G12L, G13V, and those combinations; (b) The following H-RAS mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G13D, K117N, G117T, G13C, G13C, G13S, G13S, D119N, G113N, A66T, A66T, A66T, A66T, G12A, A146V, G12N, G12R, and those combinations; (C) The following N-RAS mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13D, G13D, G13D, G13D, G12C, G12V, G12V, G12V, P185S, P185S, A146T, Q61D, A59D, A59D, A59D, E132K, E49K, T50i, A146V, A59T, and those combinations; Or, one of the above -mentioned combinations.In some embodiments, cancer includes the K-Ras mutation selected from G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L.In some embodiments, cancer includes N-RAS mutation selected from G12C, Q61H, Q61K, Q61L, Q61P, and Q61R.In some embodiments, cancer includes the H-Ras mutation selected from a group consisting of Q61H and Q61L.In some embodiments, cancer includes RAS mutations selected from G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V.In some embodiments, cancer includes at least two RAS mutations selected from groups consisting of G12C, G13C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V.In some embodiments, the compounds of the present invention inhibit two or more RAS variants.For example, compounds may inhibit both K-RAS G12C and K-Ras G13C.The compound may inhibit both N-RAS G12C and K-Ras G12C.In some embodiments, the compounds may inhibit both the K-RAS G12C and the K-Ras G12D.In some embodiments, the compounds may inhibit both the K-RAS G12V and the K-Ras G12C.In some embodiments, the compounds may inhibit both the K-RAS G12V and the K-Ras G12S.In some embodiments, the compounds of the present invention, in addition to one or more RAS mutations, and RAS. WT Inhibit (for example, K, H, or N-RAS WT Then, K-RAS G12D, G12V, G12C, G13D, G12A, G12A, Q61H, G12H, G146T, Q61L, Q61L, Q61L, Q61L, A146V, Q61F, Q61F, Q22K, Q22K, V14I, A146P, A146P, G12L, A146POr g13v; k, h, or n-ras WT Then, H-Ras Q61R, G13R, Q61K, G12L, G12L, G12D, G12D, G13V, G13V, G12C, K117N, G13T, G13C, G13C, Q61H, G13S, G13S, A146T, A66T, A146V, G12A, G12A, G12NOr G12R; or K, H, or N-Ras WT Then, N-RAS Q61R, Q61K, G12D, Q61L, Q61H, G13D, G13D, G13D, G13D, G12C, G12V, G12V, G12V, G12V, G12A, P185S, G146T, Q61P, A59D, A59D, E132K, A132K, A146V, A146V, A146V, Or A59T).In some embodiments, the compounds of the present invention, in addition to one or more RAS mutations, and RAS. amp Inhibit (for example, K, H, or N-RAS amp Then, K-RAS G12D, G12V, G12C, G13D, G12A, G12A, Q61H, G12H, G146T, Q61L, Q61L, Q61L, Q61L, A146V, Q61F, Q61F, Q22K, Q22K, V14I, A146P, A146P, G12L, A146POr g13v; k, h, or n-ras amp Then, H-Ras Q61R, G13R, Q61K, G12L, G12L, G12D, G12D, G13V, G13V, G12C, K117N, G13T, G13C, G13C, Q61H, G13S, G13S, A146T, A66T, A146V, G12A, G12A, G12NOr G12R; or K, H, or N-Ras amp Then, N-RAS Q61R, Q61K, G12D, Q61L, Q61H, G13D, G13D, G13D, G13D, G12C, G12V, G12V, G12V, G12V, G12A, P185S, G146T, Q61P, A59D, A59D, E132K, A132K, A146V, A146V, A146V, Or A59T).

[0177] The method of detecting RAS mutation is known in this technical field.Such means include direct array decisions, and, for example, THERASCREEN PCR; amoydx; pnaclamp; Realquality; Entrogen; Entrogen; Entrogen;Lightmix; stripassa; Hybcell plexa; Devyser; Surveyor; Cobas; and THERASCREEN PYRO, the whole is built into the present book, and the use of a high-sensitivity diagnosis (using the CE-IVD mark) is used.However, it is not limited to these.For example, I would like to refer to WO2020 / 106640.

[0178] In some embodiments, cancer is a non-small cell lung cancer, and RAS mutations include K-RAS mutations such as K-RAS G12C, K-Ras G12V, or K-Ras G12D.In some embodiments, cancer is colon rectal cancer, and RAS mutations include K-RAS mutations such as K-RAS G12C, K-Ras G12V, or K-Ras G12D.In some embodiments, cancer is pancreatic cancer, and RAS mutations include K-Ras mutations such as K-RAS G12D or K-Ras G12V.In some embodiments, cancer is pancreatic cancer, and RAS mutations include N-RAS mutation such as N-RAS G12D.In some embodiments, cancer is a black swelling, and RAS mutations include N-RAS mutations such as N-RAS Q61R or N-RAS Q61K.In some embodiments, cancer is non-small cell lung cancer, and RAS protein is K-RAS. amp It is.If it is not already specified, in one of the above, the compound is similar, Ras. WT (For example, K-, H-, or N-RAS WT ), Or Ras amp (For example, K-, H-, or N-RAS amp ) Can be inhibited.

[0179] In some embodiments, the cancer is RAS transformation, and STK11 LOF Includes KEAP1, EPHA5, or NF1 mutation.In some embodiments, cancer is non-small cell lung cancer and includes K-RAS G12C mutation.In some embodiments, cancer is non-small cell lung cancer, K-RAS G12C mutation and STK11. LOF Includes mutation.In some embodiments, cancer is non-small cell lung cancer, K-RAS G12C mutation and STK11. LOF Includes mutation.In some embodiments, cancer is a K-RAS G13C Ras variant, and STK11 LOF Includes KEAP1, EPHA5, or NF1 mutation.In some embodiments, cancer is non-small cell lung cancer and includes K-RAS G12D mutation.In some embodiments, cancer is non-small cell lung cancer and includes K-RAS G12V mutation.In some embodiments, cancer is colon rectal cancer and includes K-RAS G12C mutation.In some embodiments, cancer is pancreatic cancer and includes K-RAS G12D mutation.In some embodiments, cancer is pancreatic cancer and includes K-RAS G12V mutation.In some embodiments, cancer is endometrial cancer and includes K-RAS G12C mutation.In some embodiments, cancer is gastric cancer and includes K-RAS G12C mutation.In one of the above, the compounds are similar, Ras. WT (For example, K-, H-, or N-RAS WT ), Or Ras amp (For example, K-, H-, or N-RAS amp ) Can be inhibited.

[0180] It is also a method of inhibiting RAS proteins in cells, which also provides the above method, including the above method, including the above -mentioned cells in contact with the compounds of the present invention or their pharmaceutically acceptable salt.do.The above method provides the above method, including the method of inhibiting the Raf-Ras bonding, including the above-mentioned compounds of the present invention or the pharmaceutically acceptable salt.Cells can be cancer cells.Cancer cells may be any kind of cancer described in the present book.The cells may be Invibo or Invitro.

[0181] Combined therapy The method of the present invention may contain the compound of the present invention used in combination with a single or one or more additional therapy (eg, non -drug treatment or therapeutic agent).One or more additional therapy (for example, non -drug treatment or therapeutic agent) medications may be reduced from the standard medication when administered alone.For example, the dosage can be experienced from the combination and permittance of the drug, or can be estimated by isborography analysis (eg, Black et al., Neurology 65: S3-S6 (2005)).

[0182] The compounds of the present invention may be administered before, after, or at the same time as such an additional therapy.When combined, the amount of medication of the compounds of the present invention and the amount of additional treatment (eg, non -drug treatment or therapeutic agent) provide therapeutic effects (eg, synergistic or addictive therapeutic effects).do.The compounds and additional therapies of the present invention, for example, an anticancer drug can be administered in a single pharmaceutical composition, or can be administered separately, and can be administered simultaneously or continuously.Such continuous administration may be away or separated from the administration interval.

[0183] In some embodiments, additional therapy is the administration of side effects (for example, drugs intended to reduce the occurrence of side effects or severe treatment).For example, in some embodiments, the compounds of the present invention can also be used in combination with a treatment agent that treats nausea.Examples of drugs that can be used to treat nausea include Doronavinol, granisetron, metochropramide, ondanzetron, and professional chronic proladine, or those that are acceptable for those pharmaceuticals.

[0184] In some embodiments, one or more additional therapies include non -drug treatment (for example, surgery or radiation therapy).In some embodiments, one or more additional therapies include therapeutic agents (for example, anti -hemangiac, signal transmission, antipartid agents, and sugar inhibitors, or autophagy inhibitors.Includes biological formulation).In some embodiments, one or more additional therapies include non -drug treatment (for example, surgery or radiation therapy) and therapeutic agents (eg, anti -hemangiac, signal communication inhibitors, antipartulants, and sugar.Inhibitors, and include compounds or biological preparations, which are also auto -fuzzy inhibitors.In other embodiments, one or more additional therapies include two treatments.Furthermore, in other embodiments, one or more additional therapies include three treatments.In some embodiments, one or more additional therapies include four or more treatments.

[0185] In the combined therapy section, all references of the drugs described are incorporated by reference, regardless of whether they are explicitly described.

[0186] Non -drug therapy Examples of non -drug therapy include radiation therapy, freezing therapy, thermal therapy, surgical surgery (for example, surgical resection of tumor tissue), and T -cell adoption transfer (ACT) therapy, but not limited.

[0187] In some embodiments, the compounds of the present invention can be used as an auxiliary therapy after surgery.In some embodiments, the compounds of the present invention can be used as preoperative therapy before surgery.

[0188] Radiation therapy can be used in the target (eg, mammals (eg, human)) to inhibit abnormal cell proliferation, or to treat excessive proliferation disorders such as cancer.The technology for administering radiation therapy is known in this technical field.Radiation therapy can be administered by one of several methods or a combination of methods, and these methods include external beam therapy, internal radiation therapy, implant radiation, local radiation surgery, general radiation.Radiation therapy and permanent or temporary intermittent irritation therapy are not limited to these.When used in the book, the term "close contact injection therapy" is delivered by a radioactive substance trapped in a spatially inserted in the body at a tumor or other proliferative tissue disease site or near the body.Refers to radiation therapy.Although this term is not limited to these, radioactive isotope elements (for example, AT-211, I-131, I-125, Y-90, Re-186, SM-153, BI---It is intended to include exposure to 212, P-32, and LU's radioactive isotope).Radiation sources that are suitable for using as a cell adjustment of the present invention contain both solid and liquid.Inconsistent examples include radioactive nuclids such as I-125, I-131, YB-169, IR-192, I-125 as a solid source, or lightmen, beta particles, or beta particles.It may be another radioactive nuclide that emits gamma rays or other treatment rays.The radioactive substance can also be a fluid made from an I-125 or I-131 solution, or a radioactive fluid, or au-198 or Y-90, etc.It can be generated using a suitable fluid slurry containing small particles of the solid radioactive nuclide of the solid.Furthermore, radioactive nuclides (multiple) can be embodied with gel or radioactive micros fair.

[0189] In some embodiments, the compounds of the present invention can be more sensitive to radiation therapy for the purpose of killing or inhibiting such cells.Therefore, the present invention is further related to a method that makes the abnormal cells of mammal anometics sensitizable for radiation therapy, and this method is effective for letting abnormal cells sensed by radiation therapy.Includes administering to mammals.The amount of compounds in this method can be determined according to the means to confirm the valid amount of such compounds described in the book.In some embodiments, the compounds of the present invention can be used as an auxiliary therapy after radiation therapy or as a preoperative auxiliary therapy before radiation therapy.

[0190] In some embodiments, non -drug treatment is a T -cell adoption transfer (ACT) therapy.In some embodiments, T cells are activated T cells.T cells can be modified to express the chimera antigen receptor (CAR).CAR modifier T (car-t) cells can be generated by any known method in the technical field.For example, CAR-T cells can be generated by introducing a suitable expression vector encoding the car into T cells.Before the proliferation and gene modification of T cells, T -cell sources are obtained from the target.T cells can be obtained from peripheral blood nuclear cells, bone marrow, lymph nodes, umbilical cord blood, tissue, tissue from infection, ascites, pleural water, spleen tissue, and tumors.In the specific embodiment of the present invention, any number of T cells available in the technical field may be used.In some embodiments, T cells are self -T cells.Regardless of whether or after or after or after or after or after or after or after or after or after or after the gene modification of T cells to express desirable proteins (for example, CAR), T cells, for example, 6,352,694, 6,534,055, No. 6,905,680, the same 6,692,964No. 5,858,358, No. 6,887,466, the 6,905,681, the 7,144,575, the 7,067,318, the 7,067,318, the 7,172,869, No. 7,232,566, No. 7,17,243, the same No. 7,572,843, the same, the same, the same, the same, the same, the same.It can be activated and proliferated using the methods according to No. 6,905,874, the 6th, 797,514, and No. 6,867,041.

[0191] Therapeutic agent Treatment agents may be a compound used to treat the cancer or to treat the symptoms related to it.

[0192] For example, a therapeutic agent can be steroids.Therefore, in some embodiments, one or more additional therapies include steroids.Familiar steroids are 21-acetoxy pregnenolone, arcometazone, argeston, Amushinonide, Vecrometazone, Budometazone, Budetzonid, chloro-prednizon, chlorobetazol, chlorolinolon, chloroldnol, carticosteron, cortisone, cortisol, deseliza coat, deseliza coat, deseliza coat.Acetate, sodium prednizolonelin, predonnibal, predni -den, prednidene, rimexolone, chixoltol, toriham synolon acetonide, triam synolon benetonide, triam synolon benetonide, triam synolon Hexaasetonide, and their salt or guidance are not limited.。

[0193] Further examples of therapeutic agents used in combination therapies with the present invention include compounds described in the following patents: US Patent No. 6,258,812, 6,630,500, No. 6,515,004, No. 6,515,004.No. 6,713,485, 5,521,184, 5,770,599, 5,747,498, No. 5,990,141, No. 5,235,764, and 8,623,885, and international open WO01 / 3251, WO01 / 3251, WO01 / 37820, the same WO01 / 37820.No., the same WO02 / 68406, the same WO02 / 66470, the same WO02 / 55501, the same WO04 / 05279, the same WO04 / 07481, the same WO04 / 07458, the same WO04 / 09784., WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0194] The treatment agent can be a biological preparation used for the treatment of the relevant symptoms (for example, a cytokine (for example, an interferon, an interferon or an IL-2)).In some embodiments, biological formulas are an immunoglobulin biological preparation, for example, monoclonal antibodies (for example, human -based antibodies, full human antibodies, FC fusion proteins, or functional fragments).This causes a pain to the target and stimulates an anticancer response, or competes against an important antigen for cancer.It also includes antibody-drug conjugate.

[0195] The treatment agent may be a T cell checkpoint inhibitor.In one embodiment, the checkpoint inhibitor is an inhibitory antibody (for example, a single -specific antibody such as a monoclonal antibody).Antibodies can be, for example, humanization or completely human antibodies.In some embodiments, the checkpoint inhibitor is a fusion protein, for example, an FC receptor fusion protein.In some embodiments, checkpoint inhibitors are drugs such as antibodies that interact with checkpoint proteins.In some embodiments, checkpoint inhibitors are drugs such as antibodies that interact with checkpoint protein ligand.In some embodiments, the checkpoint inhibitor is a CTLA-4 (eg, anti-CTLA-4 antibody or fusion protein) inhibitor (for example, inhibitory antibodies or small molecular molecular inhibitors).In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or an antagonist (eg, inhibitory antibody or small molecular inhibitor).In some embodiments, the checkpoint inhibitor is a PDL-1 inhibitor or an antagonist (eg, inhibitory antibody or small molecular inhibitor).In some embodiments, the checkpoint inhibitor is an inhibitor or an antagonist (for example, an inhibitory antibody or FC fusion or small molecular inhibitor) of the PDL-2 (eg, PDL-2 / IG fusion protein).In some embodiments, checkpoint inhibitors include B7-H3, B7-H4, BTLA, HVEM, Tim3, GAL9, LAG3, LAG3, Vista, KIR, CD160, CGEN-15049, CGEN-15049, CHK2, A2AR, B, B.-7 Family ligand, or inhibitors or antagonists (for example, inhibitory antibodies or small molecular inhibitors).In some embodiments, checkpoint inhibitors include Pemblolismab, Nivolumab, PDR001 (NVS), REGN2810 (SANOFI / REGeneron), PD-L1 antibody, for example, Abelumab, Durvarumab, Atzorizumab, Pizligurizumab, JNJ-63723283 (JNJ-63723283, BGB-A317 (BEIGENE & CELGENE), or PREUSSER, M.ET AL., BMS936559, MEDL4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, Rillill Mab, iPH2101, 1-7F9, and KW-6002 are not limited.

[0196] The treatment agents may be anti-tigit antibodies, for example, MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (Echigiri Mab).

[0197] The drug that treats the cancer or related symptoms (for example, other compounds, which is useful for the treatment of cell poisoning, non -peptide small molecules, cancer or related symptoms.It can be a "agent").Anticancer drugs can be, for example, chemotherapy or target therapy agents.

[0198] Anticancer drugs include olive division inhibitors, insertion antibiotics, proliferation factor inhibitors, cell cycle inhibitors, enzymes, tocomerase inhibitors, biological response modifications, alkylation agents, metabolic antagonists, and folic acid.Body, Pirimidine, pudding, pudding, and related inhibitors, binka alkaloids, Epipodopilotoxin, antibiotics, L-aspalaginase, toe paragerase inhibitors, interferon, platinum co-composite, antradsgeon replacement cane, methylhidradin derivative., Cortical inhibitor, adrenocortical steroids, protrogen, estrogen, anti -estrogen, Androgen, and gonadotropin release hormones.Further anticancer drugs include Reicoboline (Lv), Ilenotecan, Oxari Platin, Capecitabin, Paclitaxel, and Doxetaxel.In some embodiments, one or more additional therapies include two or more anticancer drugs.Two or more anticancer drugs can be used in combination or for cocktails that are deducted separately.A suitable administration of the combined anticancer drug is known in the technical field, for example, Saltz et al., ProC.am.soc.clin.oncol.18: 233a (1999), and Douillard et al.Lancet 355 (9209): 1041-1047 (2000).

[0199] Other non -limited examples of anticancer drugs include Gleevec (registered trademark); Kyprolis (registered trademark) (Calfirzomib); VELCADE (registered trademark); Casodex; IRESSA(Registered trademark) (Gefichinib); Alkylation agent, for example, alkyl, sicrohos family, alkyl, sulfonate, for example, busurfan, implosul fan, piposul fan; Aziridine, for example, benzodopa, carbo -control, metsuropa, and uledo -da; ethylene;Imin and methylamelamine, for example, altain, triethylene, holamide, triethylenento -holamide, and trimethylolamelamine; acetogenin (especially bratasin and bratasinon);Briostatin; CC-1065 (for example, Adzereshin, Calzelinein, and Viselezesin synthetic bodies); Cryptoficin (specifically, Cryptoficin 1 and Cryptofishin 8); Dastertatin; Duchacal Mycin (, for example, synthesisSamurai KW-2189 and CB1-TM1); Elytherobine; Punk Lat Statatin; Sarko Stistin A; Spongy Statatin; Nitrogen Mustard, for example, chlorambusil, chloruna fajin, kolohos fajin, estramstin, mecro laurele, mecro laurele.Tamine oxide hydrochloride, melfarant, novenvitine, phentheline, predonimstin, trofos famide, and ulasyl mastard; for example, Camlustin, chlorosotoshin, hotel stin, romustin, nimstin, antibiotic, antibiotic; antibiotic; antibiotic;For example, Calikare Mycin, for example, Calcare Mycing Gamma LL and Calikare Mycin Omega LL (for example, Agnew, Chem.intl.ed Engl.33: 183-186 (1994));Bisphosphone; Esperamichanes; Neocar Ginostatin Color Color Color Color and Related Polored Protein Purse Intbalant Color Color Color, Aquarashino Mae -Shin, Authamycin, Azaseline, Breeomycin, Kakutinomycin, Charare Mycin, Charare Mycin, Charare Mycin.Rabicin, Camino Miccin, Caminomycin, Caldinomycin, Chromomycin, Daktinomycin, Daunornomycin, Detorubicin, 6-Giazo-Le-5-Oxo-Le-5-Oxo-Loicin, Adria Mycin (Doxorubicin), Morfolino-Doxorbishin, Cyanomorbishin, 2-Pilolinosorbicin, dexorbicin, dexorbicin, Epirbicin, Esorubicin, Idalbicin, Malcelomycin, Mite Mycin C, Michacophenolic acid, Nogalamiccin, Olivomycine, Olivomycine, Pipromycin, Potophilincin, Puromycin, Puromycin, Puromycin, Ceramycin, Puromycin-sinAnti-metabolites such as Zoshin, Tsubelcidine, Ubenimex, Zinostatin, Zorvish; Methotrexate and 5-Full Oro Lacil (5-FU); folic acid-like body such as Denopterine, Pteropterin, Trimetrexate;Pudding-like body; Ancitabin, Azathicidine, 6-Azauridine, Calmofur, Citarabin, Citarabin, Doxyxyuridine, Doxy Juridine, Enoshitabin, Floxyuridine, etc. Samurai Charosterone, Propionic Acid Doromo Stanronol, Epitrinol, Memi-Pichit Stan, Testrain, etc.Anti -anti -adlators such as glutechimid, mitotan, trilostan; folic acid, such as flingic acid; Acegraton; Acegraton; Acegraton; Aminolusbringil; Amusakurin; Bestravesyl; Bisandoren; DefoFamine; Defofamine;2, 2 ', 2' '-Trichlorotryethylamine; T-2 toxin, Bellaculin A, lolidine A, and Anguang-jin, etc. Torikotesen; Bindein; Dakarbasin; Mannom Stin; Mitr Bronitol; Pipobroman (GACYTOSIN) (GACYTOSIN)ARA-C "); Cyclohos Famide; Taotepa; Taxol (registered trademark) (Pakritaxel), ABRAXANE (not included in the color group, paclitaxel albumin operation nano particle preparation), and TAXOTERE (registered).Trademark) (Dokisetaxel); Crawlanbushil; Tamoki Sephen (NOLVADEX); Laroki Siphen; Aromatase Inhibitory 4 (5) -Midazole; 4-Hydroxita Moki Sphen;Trademark);-16); Ivos Famide; Mitoxantron; Bink Listin; Navelbine (Registered Trademark); Novantron; Teniposide; Edatrexate; Daonomycin; Aminopterine;; Retinoids such as retinoic acid; Esperamic acid; Capecitabin (for example, XELODA (registered trademark));

[0200] Unlimited examples of the addition of anticancer drugs include Trus Tusumab (HERCEPTIN (registered trademark)), bebasizumab (AVASTIN (registered trademark)), Cetsximab (ERBITUX (registered trademark)), and Rituximab (Rituxan (registered trademark))., TAXOL (registered trademark), ARIMIDEX (registered trademark), ABVD, Avisine, Abago Bomab, Acrygin Karboxamide, Adeca Tsum Mab, 17-N-Alluamino-17- Demetoxygeldanamycin, Alfaradin, Albosin, 3-Amino Pilidine-2-Carboxalde Hidchio Semica Calbazon, Amonafid, Antlession, anti -CD22 immunoocytes, anti -tumor drugs (for example, cell cycles non -specific anti -tumor drugs, and other antitumor drugs described in the present note), and antituments.Herb, Apagikion, Achipurimodo, Azachio Pulin, Verotecan, Vendam Stin, BIBW 2992, Birikodal, Brostalicin, Brio Statin, Bucionul Hoxymine, CBV (Chemotherapy), Calicurin, dizzclolo acoulic acid, dystery, dysmitrid, ethocodamor, ethocodamor, ethocodamor, ethocodamoridLind, Ferginol, Forodesin, Forx Festrol, ICE Chemotherapy Regimen, IT-101, Imkimod, Imkimod, Indian Bazore, Il Fulben, Larotaxel, Larotaxel, Larcandomide, Lurcanton, Lurt Tecan, Mafus Family, Mafos Family, Mitda-Dolinidine, Nadaxolin, Nafoxidin, Nafoxidin, Nafoxidin, Nafoxidin, Nafoxidin, PAC-1, Popo, Pixantron, Protea Some Inhibitor, Rebecca Micin, Resechikimod, Rubetkan, SN-38, Salinosparamid A, Salinosporiumid A, Sapacidabin, Stanford V, Swain Sonin, Talapolfin, Talapla DalTrypratin, triple (2-chloroethyl) amine, troxacita bin, ulamstin, bashamzan, binfulnin, ZD6126, and zoskidal.

[0201] Further non -limited examples of anticancer drugs include binkaarchaloids (for example, binblastin, binkuristin, vinorelbin), epidodofirotoxin (eg, etoposide and teniposide), and antibiotics (for example, DakuchinomaishinActinomycin D), Downorbicin, and idalbicin, anthrecycin, mitoxon, breomycin, pricemycin (mitramycin), mite Mycin, enzyme (eg, L-aspalagin, the ability to synthesize unique asparagin and synthesize unique asparagin.Anti-growth / anti-yarn-divisible alkylation agent such as L-asparaginase), antico-hematopenous drugs, Nitrojen mustard, and chlorolumbusil, and chlorambusl, and chlorambusl, such as anti-hematoprotinarizer), anti-hematoprotinemic drugs, and Nitrojen mustard.), Ethylenamine and methyl melamine (for example, hexamethylamelamine and tiootepa), CDK inhibitors (for example, CDK4 / 6 inhibitors such as Abemashiclibs, Ribosclibs, Palboschlibs), Celicclibs, UCN-01, PD-05, PD-05, PD-05.0332991, Dyna Clib, P27-00, AT-7519, RGB286638, SCH727965), Alkyl Sul Honate (eg, Busurfan), Nitrosoureal (for example, Calumstin (BCNU), similar body, and Street Zoshin), Folic acid -like body, pyrimidine -like body (for example, fluorowlasyl, floxyuridine, and cytarabin), anticonated / anti -yarn foliatives and relevant inhibitors (eg, Mel Captoprin, Tiooguanin, Pent.Statin, and 2-chlorodioxydenosin), aromatase inhibitors (for example, anastrosolol, exemestan, and retro zole), and platinum coordination complex (for example, cisplatin and carboplatin), professional bazine, hydroxy ultra, mitotan, mitotan, mitotan, aminoguru.Techimid, Histon Dea Cetirase (HDAC) inhibitors (for example, tricostatin, sodium, apitidan, Suberoyl Anilid hydroamic acid, Volinostat, LBH 589, Lomidepsin, ACY-1215, and pannovinostat), MTOR inhibitors (for example, Bistoceltive, Tem Silorimus, Everrims, Ridafolorimus, and Sirorimus), KSP (EG5) inhibitors (eg5)520), DNA binding agent (for example, Zalypsis (registered trademark)), PI3K delta inhibitor (for example, GS-1101 and TGR-1202), PI3K inhibitors, PI3K Delta and Gamma inhibitors (for example, Cal-130), Copan Rich, Alpelli, and Idelery Sive; Multi -Kinase Inhibitors (for example, TG02 and Sorafenib), hormones (eg, estrogen), and Loitinated hormone release hormones (LHRH) Agonists (for example, Goserelin, Roy Pro, and Treat Relin)Agonist, BAFF Medazine antibody (for example, LY2127399), IKK inhibitor, P38MAPK inhibitor, anti-IL-6 (eg, CNT0328), telomerase inhibitors (eg, GRN 163L), Aurorakinase inhibitors (eg, MLN8237),Cellular surface monoclonal antibody (for example, anti-CD38 (Humax-CD38)), anti-CS1 (eg, erotic tsumab), HSP90 inhibitor (eg, 17AAG and KOS953), P13K / AKT inhibitors (eg, perhossine), AKT inhibitors (Pelhoshin).For example, GSK-2141795), PKC inhibitors (eg, Enza Staurin), FTI (for example, Zarnestra (trademark)), anti-CD138 (eg, BT062), TORCL / 2 specific kinase inhibitors (eg, INK128),ER / UPR targeted agent (eg, MKC-3946), CFMS inhibitor (for example, Arry-382), JAK1 / 2 inhibitor (eg, CYT387), PARP inhibitors (for example, Orpalib and Veriparib (ABT-888)) And natural products such as BCL-2 antagonist.

[0202] In some embodiments, anticancer drugs are selected from Mecroletamine, Camputteshin, Ivans Famide, Tamoki Siphen, Laroki Siphen, Gemushitabin, Navelbine (registered trademark), or any of the above -mentioned similar or derivatives.

[0203] In some embodiments, anticancer drugs are HER2 inhibitors.The non -limited examples of HER2 inhibitors include monoclonal antibodies, such as trastin (registered trademarks) and Perzumab (Perjeta (registered trademark));(TARCEVA (registered trademark)), Shariitinib, CP-654577, CP-724714, Canellicinib (CI 1033), HKI-272, Lapatinib (GW-572016; Tykerb (registered trademark)), PKI-166, AEE788, BMS-599626, BMS-599626, HKI-357, Bibw 2992, Arry-334543, and JNJ-26483327.

[0204] In some embodiments, anticancer drugs are ALK inhibitors.The non-limited examples of ALK inhibitors are TAE-684 (NVP-TAE694), PF02341066 (PF02341066), Alexible, Brigatinib, Entrectinib (X-396), Lol Loltinib, ASP3026, CEP-3740, CEP-3740, CEP-3740, CEP-3740, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113.An example of the addition of an ALK kinase inhibitor is described in WO05 / 016894 Examples 3 to 39.

[0205] In some embodiments, anticancer drugs are inhibitors for members downstream of receptors tyrosine kinase (RTK) / proliferation factor receptors (eg, SHP2 inhibitors (eg, SHP099, TNO155, RMC-4550, RMC, RMC, RMC, RMC.-4630, JAB-3068, Rly-1971), SOS1 inhibitor (for example, Bi-1701963, BI-3406), RAF inhibitor, Mek inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitors, AKT inhibitors.Or MTOR inhibitor (for example, Mtorc1 inhibitor or Mtorc2 inhibitor). In some embodiments, the anticancer drug is JAB-3312. In some embodiments, anticancer drugs are., AMG 510, MRTX1257, MRTX849, JNJ-74699157 (ARS-3248), LY3499446, ARS-853, or ARS-853, or RAS vaccines, or RAS carcinogenic activity directly or indirectly.It is another treatment designed.The following examples of the RAS inhibitors that can be combined with the RAS inhibitor of the present invention are shown below, and these are all built into the present text by reference: WO2020050890, WO2020047192, WO2020035031, WO2020028706, WO2019241157, WO2019241157, WO2019241157,

[0206] In some embodiments, the therapeutic agent that can be combined with the compound of the present invention is a inhibitor (or "Mapk inhibitor") of the MAP Kinase (Mapk) route.The mapk inhibitor includes one or more Mapk inhibitors described in the Cancers (Basel) 2015 SEP; 7 (3): 1758-1784, but is not limited.RDEA 119 / Bay 86-9766), GDC-0973 / XL581, AZD8330 (Arry-424704 / Arry-704), RO5126766 (Roche, Plos ONE.2014 NOV 25; 9 (11)), and GSK1120212 (or JTP)-74057, Clin Cancer Res.2011 Mar 1; 17 (5): Described in 989-1000).Mapk inhibitors can be PLX8394, LXH254, GDC-5573, LY3009120.

[0207] In some embodiments, the anticancer drug is a destroying factor or inhibitor of Ras-raf-ERK, PI3K-AKT-Tor, or PI3K-AKT signal transmission route.The PI3K / AKT inhibitor includes one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7 (3): 1758-1784, but not limited to these.For example, PI3K / AKT inhibitors can be selected from one or more of NVP-BEZ235, BGT226, XL765 / SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, GSK2126458.

[0208] In some embodiments, anticancer drugs are PD-1 or PD-L1 antagonist.

[0209] In some embodiments, additional treatment agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-.1 Inhibitor, BCL-2 inhibitor, SHP2 inhibitor, Proteaosome inhibitor, and immunotherapy are listed.In some embodiments, the therapeutic agent can be a pan -RTK inhibitor, for example, an affatial.

[0210] The IGF-1R inhibitor includes linsitinib or its pharmaceutical salt.

[0211] The EGFR inhibitor includes a small molecular antagonist, an antibody inhibitor, or a specific anti -sensitenucleotide or SiRNA, but is not limited.Useful antibody inhibitors of EGFR include Cetsukishimab (ERBITUX (registered trademark)), Panitum Mab (VECTIBIX (registered trademark)), Salzumumab, Nimotsuzumabu, and Matsuzumabu.Further antibody -based EGFR inhibitors include any anti -EGFR antibody or antibody fragments that can partially or completely block the EGFR activation by the natural ligand.Unlimited examples of antibody-based EGFR inhibitors include Modjtahedi et al., BR.j.cancer 1993, 67: 247-253; TERAMOTO et al., Cancer 1996, 77: 639-645; Goldstein et al.Clin.cancer Res RES.1995, 1: 1311-1318; Huang et al., 1999, Cancer Res.15: 59 (8): 1935-40; and Yang et al.There is one listed in.EGFR inhibitors can be a monoclonal antibody MAB E7.6.3 (above Yang, 1999), or MAB C225 (ATCC contract number HB-8508), or an antibody or antibody fragment having their binding specificity.

[0212] EGFR's small molecular antagonist includes gefichinib (IRESSA (registered trademark)), Ellotinib (TARCEVA (registered trademark)), and lapatinib (TYKERB (registered trademark)).304 (5676): Please refer to 1497-500.In some embodiments, the EGFR inhibitor is osmeltinib (Tagrisso (registered trademark)).Further limited examples of low molecule EGFR inhibitors include one of the EGFR inhibitors described in the following patent bulletin, and all pharmaceutical salt in such EGFR inhibitors:WO99 / 35132; WO99 / 07701; and O92 / 20642.Inconspent examples of the addition of submolium EGFR inhibitors are one of the TRAXLER et al., Exp.opin.ther.patents 1998,8 (12): 1599-1625.It is listed.In some embodiments, the EGFR inhibitor is an ERBB inhibitor.In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (Neu, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0213] MEK inhibitors include pimaceltive, cellemethinib, cobemetinib (Cotellic (registered trademark)), trametinib (MEKINIST (registered trademark)), and vinylmethinib (MEKTOVI (registered trademark)), but is not limited.In some embodiments, Mek inhibitors are targeted at the Mek mutation, which is a class IMEK1 mutation selected from the D67N, P124L, P124S, and L177V.In some embodiments, Mek mutation is a class II MEK1 variable selected from ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0214] The PI3K inhibitor includes the wart manin, the 17-hydroki shiato manin-like body, 4- [2- (1H-Indazer-4-Il) -6- [4- (methylusulhonyyl) Pipelladin-1)-Il] Methyl] Chieno [3,2-D] Pirimidine-4-Il] Morholin (also known as Pictiliciv or GDC-0941 and is described in WO09 / 036082 and WO09 / 055730), 2-methyl-2- [3- [3-methyl-2-oxo-8- (quinoline-3-Il) -2,3-diphidroimidazo [4,5-c] quinoline-1-Il] phenyl] Propionic (bezIt is known as 235 or NVP-BEZ 235, and is described in WO06 / 122806), (s) -1- ((2- (2- Aminopirimidine -5-Il) -7-methyl-4-Morphorinocyeno [3,2-D] Pirimidine-6-Il) Methyl) Piperadin-1-Il) -2-Hydroxy Propane-1-on (described in WO08 / 070740)-8-phenyl-4H-1-benzopilan-4-on (available from Axon Medchem), pi 103 hydrochloride (3- [4- (4- (4- (4) Morpholinylpirid- )- [3 ', 2), 2': 4), 5] Flo [3,2-D] Pirimidine-2-Il] Phenol hydrochloride (available from Axon Medchem), pik 75 (2-methyl-5-nitro-2- [6-Bromoiimidazo [1, bromoiimidazo [1)2-A] Pyridine-3-Il) Methylene] -1-methylhydrardy-benzenzenzulfonic acid, one hydrochloride) (available from Axon Medchem), pik 90 (7,8-dimethoxy-2,3-Dihydo-Imidazo [1,2-C] Kinazolin-5-Il) -Nicotine Amide (available from AXON Medchem), AS-252424 (5- [1- [4-Fluoro-2-Hydroxy-Phenyl)-Fran-2-Il] -Meta-Iriden-Iriden] -cirodolidine-2,4-Zion (available from Axon Medchem), TGX-221 (7-methyl-2- (4-molpholinyl) -9-[1- (phenylamino) ethyl] -4H-pirid- [1,2-A] Pyrinidin-4-on (available from Axon Medchem), XL-765, and XL-147 are listed.Not done. Other PCal263, Pi-103, GNE-477, CUDC-907, and AEZS-136 are listed.

[0215] AKT inhibitors include AKT-1-1 (inhibiting AKT1) (Barnett et al., Biochem.j.2005, 385 (pt.2): 399-408);(Barnett et al., Biochem.j.2005, 385 (pt.2): 399-408);91: 1808-12); 1-H-Imidazo [4,5-C] Pyridinyl compound (for example, WO05 / 011700); Indole -3-Calvinol and its derivatives (for example, US Patent No. 6,656,963; Sarkar and AndLi J Nutr.2004, 134 (12 SUPPL): 3493S-3498S); Perhocin (for example, interfere with the AKT membrane localization; dasmahapatra et al.clin.cancer resres.2004,10 (15): 5242-52)Hosfatidyl Innocitol ether lipids (for example, gills and dennis expert.opin.in vestig.drugs 2004,13: 787-97);, Cancer Res.2004, 64: 4394-9) is listed, but not limited.

[0216] MTOR inhibitors include ATP competitive MTORC1 / MTORC2 inhibitors, for example, pi-103, pp242, pp30; torin 1; FKBP12 enhancement agent; 4H-1-benzopillan-4-on-on derivative;) And its derivatives, for example, Temshilorimus (TORISEL (registered trademark)); Everrimus (Afinitor (registered trademark), WO94 / 09010); Ridaflorimus (also known as Defolorimus or AP23573); for example, WO98 / 02441 and WO01What is disclosed in / 14387, for example, AP23464 and AP23841; 40- (2-hydroxyethyl) Lapamycin; 40- [3-hydroxymethyl (hydroxy metile) methyl propaneaite] -Lapamycin (also known as CC1779)40-Epi- (Tetrazolite) -Lapamycin (also called ABT578); 32-Deokisola Pamycin; 16-Penchinyloxy-32 (S) -Cihydrora panicine; Derivative disclosed in WO05 / 005434; US, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018 / 41807, and the derivatives disclosed in WO2018 / 204416, and the phosphorus -containing lapamycin derivatives (for example, WO05 / 016252) are listed.Not limited to.In some embodiments, MTOR inhibitors are two-dimensional inhibitors (for example, WO2018 / 204416, WO2019 / 212990, and WO2019 / 212991), for example, RMC-55552.

[0217] The BRAF inhibitors that can be used in combination with the compounds of the present invention include, for example, Vemula Fenib, Dabrafenib, and Encarfenib.BRAF can include class 3 BRAF mutation.According to some embodiments, class 3 BRAF mutation is in human braf, the following amino acid substitutions: d287h; p366v; g466v; g466a; s466a; g467l; g469ESelected from one or more of F595L; g596d; G596R; and A762E.

[0218] The MCL-1 inhibitor includes AMG-176, MIK665, and S63845, but not limited.Bone marrin cell leukemia-1 (MCL-1) protein is one of the main anti-apoptosis members of the B cell lymphoma-2 (BCL-2) protein family.The over-expression of the MCL-1 is closely related to the tumor progression and conventional chemotherapy, but also resistance to targeted drugs containing BCL-2 inhibitors such as ABT-263.

[0219] In some embodiments, the additional treatment agent is the SHP2 inhibitor.SHP2 is a non -receptor protein tyrosine phosphatase coded by the PTPN11 gene, contributing to multiple cell functions such as proliferation, differentiation, maintaining cell cycle, and moving.SHP2 has two N-terminal SRC homologous 2 domains (N-SH2 and C-SH2), catalytic domain (PTP), and C-terminal tail.The two SH2 domains control the internal and functional adjustment of SHP2.This molecule exists in an inert self-inhibitory confomination that is stabilized by a binding network involved in both the N-SH2 and PTP domain.For example, the stimulus of a cytokine or proliferation factor that acts via the receptor tyrosine kinase (RTK) leads to the exposure of the catalytic site, causing the enzyme activation of SHP2.

[0220] SHP2 is involved in the signal transmission through the RAS Mitjen activation protein kinase (Mapk), JAK-STAT, or the Hos Hoinoshitol 3-Kinase -akt route.PTPN11 gene mutations and subsequent SHP2 variants include some human developmental diseases such as Nunan syndrome and leopard syndrome, as well as young bone marrow bone -pooling leukemia, neuroblastoma, black portrait, acute myelinomy leukemia, and breast cancer.It is identified as human cancer such as lung cancer and colon cancer.Some of these mutations are unstable the self -activation of SHP2 and promote the self -activation of SHP2 or enhanced proliferation factor activation.Therefore, SHP2 is a very attractive target for the development of new therapies for treatment of various diseases, including cancer.The SHP2 inhibitor (eg, RMC-4550 or SHP099) combined with the RAS route inhibitor (eg, MEK inhibitor) is a multiple cancer cell stocks (eg, pancreatic cancer, lung cancer, ovarian, and breast cancer).It is shown to inhibit proliferation.Thus, combination therapy using SHP2 inhibitor and RAS route inhibitor can be a common strategy to prevent tumor resistance in a wide range of malignant tumors.

[0221] Unlimited examples of such SHP2 inhibitors are known in this technical field, Chen et al.mol Pharmacol.2006,70,562; Sarver et al., J.med.chem.2017,62,1793; XIEETWO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731;

[0222] In some embodiments, the SHP2 inhibitor binds to the active site.In some embodiments, the SHP2 inhibitor is a mixed irreversible inhibitor.In some embodiments, the SHP2 inhibitor binds to an allosteric site, for example, a non -shared allosteric inhibitor.In some embodiments, the SHP2 inhibitor is a shap2 inhibitor such as a targeted inhibitor targeting a cysteine residue (C333) outside the active site of the phosphatase.In some embodiments, the SHP2 inhibitor is an inverse inhibitor.In some embodiments, SHP2 inhibitors are irreversible inhibitors.In some embodiments, the SHP2 inhibitor is SHP099.In some embodiments, the SHP2 inhibitor is TNO155.In some embodiments, the SHP2 inhibitor is the RMC-4550.In some embodiments, the SHP2 inhibitor is RMC-4630.In some embodiments, the SHP2 inhibitor is JAB-3068.In some embodiments, the SHP2 inhibitor is Rly-1971.

[0223] In some embodiments, additional treatment agents are selected from a group consisting of MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, MTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors.It will be done.In some embodiments, additional treatment agents are selected from a group consisting of Mek inhibitors, SHP2 inhibitors, and PD-L1 inhibitors.For example, please refer to Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (OCTOBER 28,2019) and Canon et al., Nature, 575: 217 (2019).In some embodiments, the RAS inhibitor of the present invention is used in combination with the Mek inhibitor and the SOS1 inhibitor.In some embodiments, the RAS inhibitor of the present invention is used in combination with the PDL-1 inhibitor and the SOS1 inhibitor.In some embodiments, the RAS inhibitor of the present invention is used in combination with the PDL-1 inhibitor and the SHP2 inhibitor.In some embodiments, the RAS inhibitor of the present invention is used in combination with the Mek inhibitor and the SHP2 inhibitor.In some embodiments, cancer is a colon rectal cancer, and the treatment includes that the RAS inhibitor of the present invention is administered in combination with the second or third treatment agent.

[0224] Proposome inhibitors include Calfirzomib (Kyprolis (registered trademark)), Voltezomib (VELCADE (registered trademark)), and oprozomib, but not limited.

[0225] Immunotherapy includes monoclonal antibodies, immune-adjusted imides (imid), GitR agonists, genetic T cells (eg, car-t cells), double-specific antibodies (eg, bite), and anti-PD-1, and anti-PD-1.Anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents are not limited to these.

[0226] An immune regulator (IMID) is a class of an immune adjustment drug containing an imide group (a drug that adjusts the immune response).The imid class contains a salidomide and its similarities (lenaridomide, pomalidomide, and apremylast).

[0227] Executive anti-PD-1 antibodies and them are Goldberg et al., Blood 2007,110 (1): 186-192; Thompson et al.It is described by 1757-1761; and WO06 / 121168 A1), and in addition, it is described in other parts of the present fine text.

[0228] GitR agonists include GitR fusion proteins and anti -GitR antibodies (for example, dialogue anti -GitR antibodies), for example, US Patent No. 6,111,090, 8,586,023, WO2010 / 003118, and WO2010 / 003118, and WO2011 / 090754.The anti -GitR antibodies according to 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726 are listed.

[0229] Another example of a therapeutic agent used in combination with the compound of the present invention is an anti -hemangiac.Anti -blooded new products include chemical compositions, antibodies, antigen binding areas, radioactive nuclides, and combinations and conjugates, which are not limited to these.Anti -blooded new drugs can be a agonist, antagonist, allosteric regulator, toxins, or more generally, to inhibit or stimulate the target (for example, activate or inhibit the receptor or enzyme).However, it can promote cell death or stop cell proliferation.In some embodiments, one or more additional therapies include an anti -hemangiic new drug.

[0230] Anti-blooded new drugs are MMP-2 (Matrix-Metalo Protainase 2) inhibitors, MMP-9 (Matrix-Metalo Pro Enerase 9) inhibitors, and COX-II (Cylousoxygenase 11) inhibitors.Unlimited examples of anti-blooded new drugs include Rapamycin, Tem Sirorimus (CCI-779), Everolimus (RAD001), Solafenib, Snitinib, and Bebasizumab.Useful COX-II inhibitors include Alecoxib, Valdecoxy, and Rofe Coxib.Examples of useful matrix Metallo Protainase inhibitors are WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 33766, WO90 / 52919, WO90 / 05719, WO999 / 05719The preferred MMP-2 and the MMP-9 inhibitor have little or at all that inhibit the MMP-1.More preferred Matrix Metalo Protainase (that is, MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-10, MMP, MMPCompared to -12 and MMP-13), MMP-2 or AMP-9 selectively inhibit.Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS13-0830.

[0231] Further illustrated anti -hematophone new products include KDR (kinazedmain receptor) inhibitors (for example, antibodies and antigen binding areas that specifically binding to kinazedmain receptors), anti -VEGF (for example, VEGF (eg, VEGF).Bebasizumab), or the antibodies or antigen-binding areas specifically bonded to the soluble Vegf receptor or ligand binding region), for example, Vegf-TRAP (trademark), and anti-VEGF receptor agents (for example, specifically.Antibodies or antigen binding areas), EGFR inhibitors (for example, antibodies or antigen binding areas that bind to it), for example, vectibix (registered trademark), erlotinib (TARCEVA (registered trademark)), anti -animalAntig2 agent (for example, those receptors,, for example, antibodies or antigen binding areas that specifically bonded to TIE2 / TEK), and anti -TIE2 kinase inhibitors (for example, antigen -bonded antigenArea) is listed.Other anti-hematopathic new products include campus, IL-8, B-FGF, TEK Antagonist (US2003 / 0162712, US6,413,932), anti-Tweak agent (for example, specifically binding antibodies or antigen areas, or soluble.See TWEAK receptor antagonist, US6,727,225), ADAM Dist Integrinde Main (US2002 / 0042368), which competes for Integrine's ligand, specifically anti -EPH receptor or antiflin antibody or antigen binding area (antigen binding area (US Patent No. 5,981,245, 5,728,813, 5,969,110, No. 6,596,852, 6,232,447, 6,232,447, 6,057,124, and those patent families), and anti-PDGF-BB Antagonist (for exampleAntibodies or antigen binding areas), and antibodies or antigen-binding areas specifically bonded to PDGF-BB ligand, and PDGFR kinase inhibitors (for example, antibodies or antigen-binding areas).。Additional anti-hematopathy new products include SD-7784 (PFIZER, USA), Silement Tide (Merck KGAA, GERMANY, EPO0770622), Pegaptanib octanatium (Gilead Science, USA), Alfastatin (BIOACTA, UK), M-., IRELAND), Annecoltab (Alcon, USA), Alpha D148 MAB (Amgen, USA), CEP-7055 (Cephalon, USA), anti-VN MAB (Cephalon, USA), DAC anti-blooded new serve (CONJUCHEM, CANADA).Stealth (Johnson & Johnson, USA), Fibrinogen -E fragments (BioActa, UK), blood vessel inhibitors (Trigen, UK), TBC-1635 (Encysive Pharmaceuticals, USA), SC-236 (PFIZER, USA), SC-236 (USA), SC-236 (USA), SC-236 (USA)Abbott, USA), metastatin (Entremed, USA), masspin (SOSEI, Japan), 2-Methoxies Radio (Oncology Sciences Corporation, USA), ER-68203-00 (IV AX, USA), Benefin (Lane Lane Us), TZ-93 (TSUMURA, Japan), TAN-1120 (TAKEDA, Japan), FR-111142 (FUJISAWA, JAPAN, JP02233610), platelet 4th factor (Repligen, USA, EP407122), blood vessel breeding factor (BOREAN, BOREAN, BOREAN.DenMark), Bebasizumab (Genentech, USA), vascular inhibitors (SUGEN, USA), XL 784 (EXELIXIS, USA), XL 647 (EXELIXIS, USA), MAB, Alpha 5 Beta 3 Integrine, 2nd generation (2nd generationFoundation, USA), SPV5.2 (SEISAI, Japan), CYC 381 (HARVARD UNIVERSITY, USA), AE 941 (AETERNA, CANADA), vaccine, blood vessels (ENTREMED, USA), Urokinase plus minogen activation factor inhibitory inhibitors (DENDREON, USA).(Pinn) (Melmotte, USA), HIF-LALFA inhibitor (Xenova, UK), CEP 5214 (Cephalon, USA), Bay Res 2622 (Bayer, Germany), Anggio Chidin (Inkine, USA), A6 (A6 (ANGSTROM)(Abbott, USA), AAL 993 (Novartis, Switzerland), VEGI (Proteomt)Ech, USA), tumor necrosis causes-alpha inhibitors, su 11248 (pfizer, USA and SUGEN, USA), ABT 518 (abbott, USA), YH16 (Yantai Rongchang, China), S-3apg (Boston Childrens Hospits, S-3apg (Boston Childrens)USA and Yale University, USA), CS 706 (SANKYO, Japan), Conbret Statatin A4 Pro Drug (ARIZONA STATE UNIVERSITY, USA), Chondroitinase AC (IBEX, CANADA), Bay RES 2690 (BAYERIvy Medical, UK), CKD 732 (CHONG KUN DANG, South Korea), Ilsogram (NIPPON SHINYAKU, JAPAN), RG 13577 (Aventis, France), WX 360 (WILEX, GERMANY), Sculamine (GENAERA), Scalamine.(SIRNA, USA), Heparanase Inhibitor (Insight, ISRAEL), KL 3106 (Kolon, South Korea), Honokiol (Emory University, USA), ZK CDK (Schering Ag, Germany), ZK Ango (Schering Ag, Germany), Zk Angio (Germany)ZK 229561 (Novartis, Switzerland and Schering AG, Germany), XMP 300 (XOMA, USA), VGA 1102(TAISHO, Japan), VE-Cadhelin-2 Antagonist (IMCLONE SYSTEMS, USA), Basso Statin (NATITITUTES OF HEALTH, USA), FLK-1 (IMCLONE SYSTEMS, USA), TZ 93 (TZ 93 (TSUMURA) (TSUMURA), USA)ISRAEL HOSPITAL, USA), short-type soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA), TIE-2 ligand (Regeneron, USA), and trombbo. Sponjin 1 inhibitor (Allgheny Health, Education and Research Foundation, USA) is listed.

[0232] Further examples of therapeutic agents used in combination with the compounds of the present invention are specifically binding and inhibiting the activity of proliferation factors such as antagonists (HGF, scattered factor).Antibodies or antigen binding areas specifically binding to the antibody, antigen binding area, or soluble receptor), and the receptor C-MET.

[0233] Another example of a therapeutic agent used in combination with the compound of the present invention is an autophagy inhibitor.Autophagi inhibitors include chlorokin, 3-methyl adenin, hydroxyclorokin, Baphiromycin A1, 5-Amino-4-Amidazole Calboxamido Riboside (AICAR), Okada acid, 2A type or 1 type.There are drugs that increase the CAMP level, such as autophagy-suppressed algae toxins that inhibit the protein phosphatase, CAMP-like body, and adenosine, LY204002, N6-Mercaputoprine riboside, and binbrastine, but this is not limited.In addition, anti -sense or SiRNA, which contains ATG5 (related to autophagy) but not limited to these proteins, can also be used.In some embodiments, one or more additional therapies include an autophagy inhibitor.

[0234] Another example of a therapeutic agent used in combination with the compound of the present invention is an antimartial tumor agent.In some embodiments, one or more additional therapies include an antimalmic tumor.Unlimited examples of antimalmic tumor agents include Ashemannan, Aquaralvicin, Ardesloikin, Alemutuzumabu, Aremtsumabu, Altretamine, Altretinin, Aminolibulinic acid, Amulbicin, Amulbicin, Anaglerid, Anastridol, Anaser (ANCER)Uncare, BAM-002 (Novelos), Bexaroten, Vicarotamide, Blur modexyuridine, Capecitabin, Celmorokin, Cettrolicus, Clator Ribin, Crotrimazol, Citarabin OK Hosfate, DA 3030 (DONG-A), Epirbicin, Epoethinbator, Epoethinbuta, Enpoethinida, Enxy Mestin, Exisrind, Fadrosole, Filglastim, Finasteride, Finasteride, Finasteride, Fulglastine, Holemestine, Hotemstin, Gemcitabin, Gemzumabzamycin, Gimszumabzamycin, Gimelasil / TegafurCombination, glycopin, goserelin, hepta platin, human chorion gonadotropin, human fetal alpha acid, Idalbic acid, Idalbic acid (Imikimodo, interferon alpha, natural type, interferon alpha-2A, interferon alpha-2A, interferon alpha-2A, interferon alpha-2A, interferon alpha-2A, interferon alpha-2A.Interferon Alpha-Ni, interferon Alpha-N3, interferon alpha-one, interferon alpha, natural, interferon beta, interferon beta, interferon beta, interferon gamma, natural interferon gamma -LA, interferon gamma -LB,Interroikin-1 beta, Ibean, Illinotecan, Illinotecan, Ilsograph, LC9018 (YAKULT), Reflenomide, Lengrastim, Sulfate Rentinan, Retrozor, White Blood Ball Alfine Turry, Ryu Pro LoreliN, Levamizol+Full Oro -Rasil, Liarosole, Roba Pratin, Ronidamine, Ronidamine, Robastatin, Masoprocol, Metocrplamide, Mefepramide, Mipeprramide, Milltahosin, Mirimostim, Miss Miss Double Chain RNA, Mitg Azon, Mitrica Santol, Mitoxon Ron, Mitoxon Ron, Mitoxon Ron, Naroxon+Pentazoshin, Naruto Glastim, Neda Platin, Neiltamide, Noscapine, new red blood cell production promotion proteins, NSC631570 Otreotide, Opurberdong, Oxari Platin, Pacritaxel, Pamidron Rodent, Peguinsparse, Peguin Parse, Peguinsparse, Peguinsparse, Peguinsparse, Toremifen, Toshitomo Mab-iodine 131, Torusuzumab, Treosul Fan, Tretinoin, Tretinin, Trimetrexate, Tripreline, Tumor Necrosis Factor Alpha, Ubenimics, Bladder Cancer Vouchine, Maruyama Vakutin, Black Sempto Surzen Vallebishin, Valulvicine.Beltepolphin, Vinolavin, Binoleridine, Zinostatinsutomaramar or Zoledronic acid; Avarelix; Ae941 (AETERNA), Ambumstin, Anti-Sense Oligonucleotide, BCL-2 (GENTA), APC8015 (DENDREON), Decitabin, Decitabin, Decitabin, Decitabin, Decitabin, Decitabin, Decitabin, Decitabin, Decitabin, Decitabin, DecitabinGiajicon, EL532 (ELAN), EM800 (ENDORECHERCHE), Enil Urasil, Etanidazole, Fen Retinide, Philglass Chim SD01 (Amgen), Full Bestrant, Garositabin, Gastlin 17 Imnogen,HLA-B7 gene therapy (VICAL), granulocyte macrophage colony stimulus factor, histamine dinoglite, Iburitsumo mabuchi uquisethane, Iromastat, IM862 (Cytran), interloykin-2, iProxifen, LDI200 (Milkhaus), RergissistimTechNICLone), Multippedent Either Muchin-Ichet Rium 90mab (Antisoma), Marimastat, Menogalil, Mitsu Momab, Motexafin, Gadolinium, MX6 (GALDERMA), Nerarabin, Noratrexed, P30 protein, Pegbisoman, Pemetrey Manto, Pemetrin Seda, PemetreykesomanRL0903 (Shire), rubytecan, Satrapratin, phenyl acetate, sparrow acid, SRL172 (SRPHARMA), SU5416 (SUGEN), TA077 (TANABE), Tetra Laomoribin, Tetra Laomoribin, Sribrasutin, Sribrolastin, Tronzo Popoethin, Su5416, Sribrus Pulin, Suzuzenyul Pulton, Suzuethyl Prophe, Suzuzenyul Purus, Suzoethyl Pulator, Suzuzenyul Purus, Suzuethyl Pulstin, Suzuzenyul Purus, Suzuzenyul Purus, Suzuzenyul Purastin, Or Valspodal is listed.

[0235] Examples of the addition of therapeutic agents used in combination with the compounds of the present invention include Ipirimbu (YERVOY (registered trademark)); Treming Mab; Nivol Mab, BMS-936558 (OPDIVO (registered trademark));Ad-Torasutsumabumtansin (KADCYLA (registered trademark)); Afuri Velseb (EYLEA (registered trademark)); Aremutuzumabu (Campath (registered trademark)); Basilicimab (Simulect (registered trademark)); Belim Mab (Benlysta)Bashiriximab (Simulect (registered trademark)); Verim Mab (Benlysta (registered trademark)); Brentaximabedotin (Adcetris (registered trademark)); Kanakinumabu (ILARIS (registered trademark));Trademark));Tsuzumabuosogamisin (MyLotarg (registered trademark)); Gorimmab (SIMPONI (registered trademark)); Ibretsmobutchi Kisetan (Zebalin (registered trademark)); Infriximab (Remicade (registered trademark)); Motabizumab (registered (registered)Trademark); Natalizumab (TYSABRI (registered trademark)); Obinotsuzumabu (GAZYVA (registered trademark)); Oppatum Mab (ARZERRA (registered trademark)); Omarizumab (XOLAIR (registered trademark));Tsuzumab (Perjeta (registered trademark)); Pelta Mab (Perjeta (registered trademark)); Ranibizumabu (Lucentis (registered trademark)); Laxibakumab (ABTHRAX (registered trademark));-131; Toshitsumumabu and Toshitsu Mab -i-131 (BEXXAR (registered trademark)); Ustekinumabu (Stelara (registered trademark)); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745;It is.

[0236] The compounds described in the present book can be used in combination with the drug disclosed in the head book or other suitable drugs, depending on the treatment.Thus, in some embodiments, one or more compounds of the present disclosure will be administered simultaneously with other therapies as described in the book.When used in combination therapy, the compound described in the present book may be administered simultaneously or separately as the second drug.This combination may include simultaneous administration of two drugs in the same dosage form, simultaneous administration with separate dormitory forms, and separate administration.That is, the compound described in the present book and any drug described in the present metropolis can be made together in the same dosage form and can be administered at the same time.Alternatively, the compounds of the present invention and any therapy described in the present metropolis can be administered at the same time, and both drugs exist in separate preparations.In another alternative method, the compound of the present disclosure can be administered, followed by any therapy described in the present note, and vice versa.In some embodiments of the separate administration protocol, any therapy according to the compounds and the current metropolitanes of the present invention is administered at a few minutes, or several hours, or a few days.

[0237] In some embodiments of the method described in this book, the first therapy (eg, the compound of the present invention) and one or more additional therapies are simultaneous or continuous in any order.It is administered.The first therapeutic agent is just before or immediately after or immediately after one or more treatment, or up to 1 hour, 2 hours, up to 3 hours, up to 4 hours, up to 6 hours, up to 7 hours, up to 7 hours, up to 7 hours.8 hours, 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, up to 14 hours, up to 16 hours, up to 17 hours, up to 17 hours, up to 20 hours, up to 21 hours, Up to 22 hours, up to 23 hours, up to 24 hours, or on the front and rear up to 1 ~ 7, 1 ~ 14, 1 ~ 21, or on the first to 30 days.

[0238] The present invention also implements any of the pharmaceutical compositions, including the drug (eg, the compound of the present invention), and (b) the method described in the present book.It features a package with inserted instructions and kits containing.In some embodiments, the kit is a pharmaceutical composition containing the drug (for example, the compound of the present invention) in the (a) category (for example, b) an additional therapy (b).Includes a treatment or a treatment agent) and a package inserted with an instructions for implementing any of the methods described in the (c) specified method.

[0239] One embodiment of the present invention is to intend to treat diseases or related symptoms related to pharmaceutical compounds that can be administered separately.It is further related to combining.The kit can include two separate pharmaceutical compositions, that is, the compounds of the present invention, and an additional therapy.The kit may contain a container for housing separate compositions such as split bottles or split foil packets.Examples of the addition of containers include a syringe, a box, and a bag.In some embodiments, the kit may have an instructions for using separate ingredients.The kit form is preferably administered in a different pharmaceutical form (eg, oral and non -oral), and is administered at different medication intervals, or a deduction of each ingredient in the combination.It is especially advantageous when desired.

[0240] Unract embodiment [1] Compound having a structure of equation I, or its pharmaceutical salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-or> C = CR 9 R 9’ [In the formula, carbon is -n (r) 11 C (o)-, 3 to 6 cycloalene, arbitrarily replaced, 3 to 6 heterocycloalene, six Alrain, or 5-6 members.It is bonded to the heteroseurelene carbonyl carbon.] G is an arbitrarily replaced C 1 -C 4 Alkylene, arbitrarily replaced C 1 -C 4 Alkenylene, arbitrarily replaced C 1 -C 4 Heterocyulene, -c (o) o-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], -C (o) nh-ch (r) 6 )-[In the formula, C is -c (R) 7 R 8 ) -It binds to.], C in arbitrarily replaced 1 -C 4 Heterocyulene or 3-8 heteralen, L does not exist, or a linker, W is hydrogen, cyanos, arbitrarily replaced amino, and arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkyl, arbitrarily replaced, 6 to 10 aril, or arbitrarily replaced.8 Heterailir of the member, X 1 Is an arbitrarily replaced C 1 -C 2 Alkylene, NR, O, or S (O) n , X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 CH, CH 2 , Or N, Y 6 C (o), ch, ch 2 , Or N, R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 Alyl or hetereril of 5 to 10 members that are arbitrarily replaced R 1 And R 2 Forms a heterocycloalchill for 3 to 14 members that are arbitrarily replaced with the bonded atoms. R 2 Do not exist, hydrogen, arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 6 cycloalkyl, arbitrarily replaced 3 to 7 heterocycloalkyl, six arils of arbitrarily replaced, 5 or 6 Hetero.Alill, R 3 Does not exist or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7a And R 8a Is independent, hydrogen, halo, arbitrarily replaced c 1 -C 3 It is alkyl or combined with the carbon in which they bind, forming carbonyyl. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Hydrogen, F, arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced R 9 And L forms a heterocycloalkyl for 3 to 14 members that are arbitrarily replaced with the atoms they bind. R 9’ Is hydrogen or arbitrarily replaced c 1 -C 6 Alkyl, R 10 Is hydrogen, halo, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, R 10a Is hydrogen or halo, R 11 Is hydrogen or c 1 -C 3 Alkyl, and R 16 Is hydrogen or c 1 -C 3 Alkyl.].

[0241] [2] G is arbitrarily replaced c 1 -C 4 Heterocyulene compounds described in paragraph [1], or their pharmaceutical salt.

[0242] [3] The compound described in paragraph [1] or [2], where the above compound has the structure of the equation IC, or its pharmaceutical salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, carbon is -n (r) 11 C (o)-, 3 to 6 cycloalene, arbitrarily replaced, 3 to 6 heterocycloalene, six Alrain, or 5-6 members.It is bonded to the heteroseurelene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. X 2 Is O or NH, X 3 Is n or ch, N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 And y 6 Is independent, ch or n R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 Hydrogen, C in arbitrarily replaced 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, 3 to 6 cycloalkyl, arbitrarily replaced 3-7 heterocycloalkyl, 6 aril of arbitrarily replaced, 5 or 6 Hetero.Alill, R 3 Does not exist or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced R 10 Hydrogen, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl, and R 11 Is hydrogen or c 1 -C 3 Alkyl.].

[0243] [4] x 2 The compound described in one of the NH, paragraph [1] to [3], or its pharmaceutical salt.

[0244] [5] x 3 The compound described in one of the CH, paragraph [1] to [4], or its pharmaceutical salt.

[0245] [6] r 11 The compound described in one of the hydrogen, paragraphs [1] to [5], or their pharmaceutical salt.

[0246] [7] r 11 C 1 -C 3 The compound described in one of the alkyl, paragraphs [1] to [5], or their pharmaceutical salt.

[0247] [8] r 11 Methyl, the compound described in the paragraph [7], or its pharmaceutical salt.

[0248] [9] The compound with a paragraph [1] to [6], where the compound has a structure of the equation ID, or its pharmaceutical salt: [Formation] [During the formula, the dotted line indicates 0, 1, 2, 3, or four non -indigenous double bonds, A is -n (h or ch 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. N is 0, 1, or 2 R is hydrogen, cyanos, and arbitrarily replaced C. 1 -C 4 Alkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, C (O) R ', C (O) or', C (O) N (R ') 2 , S (O) R ', S (O) 2 R 'or S (O) 2 N (R ') 2 , Each R 'is independent, H or arbitrarily replaced c 1 -C 4 Alkyl, Y 1 Is C, Ch, or N Y 2 , Y 3 , Y 4 , And y 7 Is independent, C or N, Y 5 And y 6 Is independent, ch or n R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 Hydrogen, C in arbitrarily replaced 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, 3 to 6 cycloalkyl, arbitrarily replaced 3-7 heterocycloalkyl, 6 aril of arbitrarily replaced, 5 or 6 Hetero.Alill, R 3 Does not exist or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 4 Not existed, metilled arbitrarily replaced by hydrogen, halogen, cyanos, or 1-3 halogen. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl, or heterocycloalchill of 3 to 7 members that are arbitrarily replaced. R 10 Hydrogen, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl.].

[0249]

[10] x 1 However, C was arbitrarily replaced 1 -C 2 The compounds described in one of the alkirene paragraphs [1] to [9], or their pharmaceutical salt.

[0250]

[11] x 1 The compound described in the paragraph

[10] , which is a methylene, or its pharmaceutical salt.

[0251]

[12] R 5 The compound described in one of the hydrogen, paragraphs [1] to

[11] , or their pharmaceutical salt.

[0252]

[13] r 5 However, C was arbitrarily replaced by halogen 1 -C 4 The compounds described in one of the alkyl, paragraphs [1] to

[11] , or their pharmaceutical salt.

[0253]

[14] R 5 The compound described in the methyl, the paragraph

[13] , or its pharmaceutical salt.

[0254]

[15] Y 4 The compound described in one of the C, the paragraph [1] to

[14] , or its pharmaceutical salt.

[0255]

[16] r 4 The compound described in one of the hydrogen, paragraphs [1] to

[15] , or their pharmaceutical salt.

[0256]

[17] Y 5 The compound described in one of the CH, paragraph [1] to

[16] , or its pharmaceutical salt.

[0257]

[18] Y 6 The compound described in one of the CH, paragraph [1] to

[17] , or its pharmaceutical salt.

[0258]

[19] Y 1 The compound described in one of the C, the paragraph [1] to

[18] , or its pharmaceutical salt.

[0259]

[20] Y 2 The compound described in one of the C, the paragraph [1] to

[19] , or its pharmaceutical salt.

[0260]

[21] Y 3 The compound described in one of the paragraphs [1] to

[20] , which is n, or its pharmaceutical salt.

[0261]

[22] r3 The compound described in one of the paragraphs [1] to

[21] , which does not exist, or its pharmaceutical salt.

[0262]

[23] Y 7 The compound described in one of the C, the paragraph [1] to

[22] , or its pharmaceutical salt.

[0263]

[24] The compound has the structure of the equation IE, paragraph [1] to [6], or [9] to

[23] , or its pharmaceutical salt: [Formation] [In the formula, A is -n (h or ch) 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 Hydrogen, C in arbitrarily replaced 1 -C 6 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, 3 to 6 cycloalkyl, arbitrarily replaced 3-7 heterocycloalkyl, 6 aril of arbitrarily replaced, 5 or 6 Hetero.Alill, R 3 Does not exist or R 2 And R 3 Forms a cycloalual kill for 3 to 8 members or arbitrarily replaced, combined with the atoms they bind, formed. R 5 Is an arbitrarily replaced in hydrogen and halogen. 1 -C 4 Alkyl, cyano, hydroxy, or C 1 -C 4 Alcooxy, cyclopropyl, or cyclobotile, R 6 Is hydrogen or methyl, R 7 Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl or or R 6 And R 7 Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 8 Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7 And R 8 Combined with the carbon atoms that they join, C = CR 7’ R 8’ , C = N (OH), C = N (O-C) 1 -C 3 Alkyl), C = O, C = S, C = Nh, and 3 to 6 cycloalkills, or 3 to 7 heterocycloalchills formed arbitrarily substituted. R 7’ Hydrogen, halogen, or arbitrarily replaced C. 1 -C 3 Alkyl, R 8’ Hydrogen, halogen, hydroxy, cyano, arbitrarily replaced c 1 -C 3 Alcoxy, arbitrarily replaced C 1 -C 3 Alkyl, arbitrarily replaced C 2 -C 6 Alkenyl, arbitrarily replaced C 2 -C 6 Alquinyl, 3 to 8 cycloalkyl, arbitrarily replaced 3 to 14 heterocycloalkyl, 5 to 10 heteriles, or arbitrarily replaced 6Oral of ~ 10, or R 7’ And R 8’ Forms a cycloaloyal kill for 3-6 members, or a 3-7 heterocyroal kill, which is arbitrarily replaced with the carbon atoms. R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl, or heterocycloalchill of 3 to 7 members that are arbitrarily replaced. R 10 Hydrogen, hydroxy, C 1 -C 3 Alcooxy or C 1 -C 3 Alkyl.].

[0264]

[25] r 6 The compound described in one of the hydrogen, paragraphs [3] to

[24] , or their pharmaceutical salt.

[0265]

[26] r 2 Hydrogen, cyano, arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced cycloalocyl, or a compound described in one of the paragraphs [1] to

[25] , which is a 3-6 heterocycloalkyl, which is arbitrarily replaced., Or its pharmaceutical salt.

[0266]

[27] r 2 Was arbitrarily replaced 1 -C 6 The compounds described in the paragraph

[26] , which are alkyl, or their pharmaceutical salt.

[0267]

[28] r 2 The compound described in the paragraph

[27] , which is ethyl, or its pharmaceutical salt.

[0268]

[29] r 7 However, C was arbitrarily replaced 1 -C 3 The compound described in one of the alkyl, paragraphs [1] to

[28] , or their pharmaceutical salt.

[0269]

[30] r 7 C 1 -C 3 The compounds described in the paragraph

[29] , which are alkyl, or their pharmaceutical salt.

[0270]

[31] r 8 However, C was arbitrarily replaced 1 -C 3 The compound described in one of the alkyl, paragraphs [1] to

[30] , or their pharmaceutical salt.

[0271]

[32] r 8 C 1 -C 3 The compounds described in the paragraph

[31] , which are alkyl, or their pharmaceutical salt.

[0272]

[33] The compound with a paragraph [1] to

[32] , where the compound has the structure of equation IF, or its pharmaceutical salt: [Formation] [In the formula, A is -n (h or ch) 3 ) C (o)-(ch 2 )-[In the formula, amino nitrogen is -ch (r) 10 )-), 3 to 6 members of 3 to 6 members, 3 to 6 heterocycloalene of 3 to 6 members, six Alrain, or arbitrarily replaced 5 ~ 6.It is bonded to the carbon atom of the Hetero Allylene.] B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 1 Ciano, C, is an arbitrarily replaced C. 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~It is 10 aryl of 10 or 5 to 10 hetererirs, which are arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, and R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, or 3 to 7 heterocyroquills for arbitrarily replaced.].

[0273]

[34] r 1 The compounds described in one of the 5 to 10 hetereril, which is a heteroalyl, or the pharmaceutically acceptable salt.

[0274]

[35] r 1 However, the compounds described in the paragraph

[34] , which are arbitrarily substituted or heteroalyl, which is arbitrarily replaced, or the pharmaceutical salt.

[0275]

[36] The compound with an equation IG, a paragraph [1] to

[35] , or its pharmaceutically acceptable salt: [Formation] In the formula, A is an arbitrarily replaced cycloalen, 3 to 6 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced.It ’s a 5-6 heterearlen, B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced X e N, ch, or CR 17 , X f Is n or ch, R 12 Is an arbitrarily replaced C 1 -C 6 Alkyl or arbitrarily replaced C 1 -C 6 Heterocyl, and R 17 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 aryls or hetererirs of 5 to 10 members arbitrarily replaced.].

[0276]

[37] x e Is n, x f The compound described in the paragraph

[36] , which is CH, or its pharmaceutical salt.

[0277]

[38] x e Is CH, x f The compound described in the paragraph

[36] , or its pharmaceutically acceptable salt.

[0278]

[39] x e CR 17 And X f The compound described in the paragraph

[36] , or its pharmaceutically acceptable salt.

[0279]

[40] R 12 However, C was arbitrarily replaced 1 -C 6 The compounds described in one of the heter alkill, paragraphs

[36] to

[39] , or their pharmaceutical salt.

[0280]

[41] r 12 But [Formation] The compound described in one of the paragraphs

[36] to

[40] , or their pharmaceutical salt.

[0281]

[42] The compound with a paragraph [1] to

[41] , which has the structure of the equation IH, or its pharmaceutical salt: [Formation] In the formula, A is an arbitrarily replaced cycloalen, 3 to 6 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced.It ’s a 5-6 heterearlen, B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkills, or heterocyroquills of 3 to 7 members that are arbitrarily replaced X e , CH, or CR 17 And, and R 17 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, 3 to 6 cycloalkenyl, arbitrarily replaced heterocycloalkyl, arbitrarily replaced, 6 ~10 aryls or hetererirs of 5 to 10 members arbitrarily replaced.].

[0282]

[43] The compound with a paragraph [1] to

[42] , where the compound has the structure of equation II, or its pharmaceutically acceptable salt: [Formation] In the formula, A is an arbitrarily replaced cycloalen, 3 to 6 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced.It ’s a 5-6 heterearlen, B is -ch (r) 9 )-[In the formula, the carbon is -nhc (o)-, 3 to 6 cycloalene of 3 to 6 members, 3 to 6 heterocycloalene, arbitrarily replaced, 6 members.It is bonded to Allylene or 5-6 Hetero Allylene carbonyl carbon.] L does not exist, or a linker, W is a hydrogen, an arbitrarily replaced amino, and an arbitrarily replaced C. 1 -C 4 Alcoxy, arbitrarily replaced C 1 -C 4 Hydroxyalkyl, arbitrarily replaced C 1 -C 4 Amino Alkyl, arbitrarily replaced C 1 -C 4 Hello alkill, arbitrarily replaced C 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 4 Guanidino Alkyl, C 0 -C 4 Alkyl, 3 to 11 heterocycloalchill, 3 to 8 cycloalkills, or heteroarir of 3 to 8 members arbitrarily replaced. R 2 , C 1 -C 6 Alkyl or 3-6 cycloalkyl, R 7 , C 1 -C 3 Alkyl, R 8 , C 1 -C 3 Alkyl, and R 9 Is an arbitrarily replaced C 1 -C 6 Alkyl, arbitrarily replaced C 1 -C 6 Heterocyl, 3 to 6 cycloalkyl of 3 to 6 members, or 3 to 7 heterocyroquills for arbitrarily replaced.].

[0283]

[44] A compound described in one of the six Alrain, which is arbitrarily replaced, Alrain, paragraph [1] to

[43] , or its pharmaceutical salt.

[0284]

[45] A compound described in paragraph

[44] with the following structure, or its pharmaceutical salt: [Formation] [In the formula, R 13 Hydrogen, hydroxy, amino, cyano, arbitrarily replaced C 1 -C 6 Alkyl or arbitrarily replaced C 1 -C 6 It is a heter alkill.].

[0285]

[46] r 13 The compound described in the paragraph

[45] , which is hydrogen, or its pharmaceutical salt.

[0286]

[47] r 13 The compound described in paragraph

[45] , which is a hydroxy, or its pharmaceutical salt.

[0287]

[48] A compound described in one of the paragraphs [1] to

[43] , which is an arbitrarily substituted heteroseuren, or a pharmaceutical salt.

[0288]

[49] A [Formation] The compound described in the paragraph

[48] , or its pharmaceutically acceptable salt.

[0289]

[50] A [Formation] The compound described in the paragraph

[49] , or its pharmaceutically acceptable salt.

[0290]

[51] b is -chr 9 -S, the compounds described in one of the paragraphs [1] to

[50] , or their pharmaceutical salt.

[0291]

[52] r 9 However, C was arbitrarily replaced 1 -C 6 Alkyl or arbitrarily substituted cycloalkyl, a compound described in paragraph

[51] , or its pharmaceutical salt.

[0292]

[53] r 9 But [Formation] The compound described in the paragraph

[52] , or its pharmaceutically acceptable salt.

[0293]

[54] r 9 But [Formation] The compound described in the paragraph

[53] , or its pharmaceutically acceptable salt.

[0294]

[55] B is a compound described in one of the six Alrain, which is arbitrarily replaced, paragraph [1] to

[50] , or its pharmaceutical salt.

[0295]

[56] The compounds described in

[55] , or their pharmaceutical salt.

[0296]

[57] B [Formation] The compound described in the paragraph

[56] , or its pharmaceutically acceptable salt.

[0297]

[58] The compound described in one of the paragraphs [1] to

[50] , or the pharmaceutical salt that does not exist.

[0298]

[59] r 7 The compound described in one of the methyl, paragraphs [1] to

[58] , or their pharmaceutical salt.

[0299]

[60] r 8 The compound described in one of the methyl, paragraphs [1] to

[59] , or their pharmaceutical salt.

[0300]

[61] The compound described in one of the paragraphs [1] to

[60] , which is the structure of equation II, or its pharmaceutical salt: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Equation II [In the formula, A 1 Is the bond between the linker and the B; a 2 Is a bond between W and the linker; b 1 , B 2 , B 3 , And B 4 Each is independent and is arbitrarily replaced. 1 -C 2 Alkylene, arbitrarily replaced C 1 -C 3 Heterocyulene, O, S, and NR N Selected from; r N Hydrogen, C in arbitrarily replaced 1 -C 4 Alkyl, arbitrarily replaced C 1 -C 3 Cycloalkyl, arbitrarily replaced C 2 -C 4 Alkenyl, arbitrarily replaced C 2 -C 4 Alquinyl, arbitrarily replaced heterocycloalchill, arbitrarily replaced aryl, or arbitrarily replaced. 1 -C 7 Heterocyl; c 1 And C 2 Selected from carbonyyl, thiocarbonyl, sulfonyl, or phosphoryl, each of which is independent; F, G, H, I, J, and K are independent, 0 or 1. 1 Is an arbitrarily replaced C 1 -C 10 Alkylene, arbitrarily replaced C 2 -C 10 Alkenylene, arbitrarily replaced C 2 -C 10 Alquinylene, 3 to 14 heterocycloalene, arbitrarily replaced, 5 to 10 hetererlene, 3 to 8 cycloalquils, arbitrarily replaced, 6 ~ 10.Arielen of the member, C, is an arbitrarily replaced C 2 -C 10 Polyethylene glycorene or C in arbitrarily replaced 1 -C 10 Heterocyulene or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h --- (b 3 ) i -(C 2 ) j -(B 4 ) k -A 2 It is a chemical bond to bind to.].

[0301]

[62] The compounds described in one of paragraphs [1] to

[61] , which are non -ringing, or their pharmaceutical salt.

[0302]

[63] The compound described in the paragraph

[62] , which has the structure of equation IIA, or its pharmaceutical salt: [Formation] [In the formula, x a Does not exist, or n, R 14 Does not exist, hydrogen, arbitrarily replaced c 1 -C 6 Alkyl or arbitrarily replaced C 1 -C 3 Cycloalkyl, and L 2 Does not exist, -c (o)-, --so 2 -, A arbitrarily replaced C 1 -C 4 Alkylene or arbitrarily replaced C 1 -C 4 Heterocyane, X a , R 14 , Or L 2 There is at least one of them.].

[0303]

[64] The compound described in the paragraph

[63] with the following structure with the following structure, or its pharmaceutical salt: [Formation]

[0304]

[65] The compound described in the paragraph

[64] , which has the following structure with the following structure, or its pharmaceutical salt: [Formation]

[0305]

[66] The compounds described in one of the above -mentioned linkers or the paragraphs [1] to

[61] , or their pharmaceutical salt.

[0306]

[67] The compound described in one of the paragraphs [1] to

[61] or

[66] , which has the structure of equation IIB, or its pharmaceutical salt: [Formation] [In the formula, O is 0 or 1, X b C (o) or so 2 , R 15 Is hydrogen or arbitrarily replaced c 1 -C 6 Alkyl, CY is an arbitrary 3 to 8 cycloalen, 3 to 8 heterocycloalene, an arbitrarily replaced Alrain, or an arbitrarily replaced 5 ~.10 Heteralen, and L 3 Does not exist, -c (o)-, --so 2 -, A arbitrarily replaced C 1 -C 4 Alkylene or arbitrarily replaced C 1 -C 4 Heterocyane.].

[0307]

[68] The compound described in the paragraph

[67] , which has the following structure with the following structure, or its pharmaceutical salt: [Formation] [Formation]

[0308]

[69] The compound described in one of the paragraphs [1] to

[68] , which is a hydrogen, or the pharmaceutical salt.

[0309]

[70] The compound described in one of the amino, which is an amino that is arbitrarily replaced, is a compound described in one of one of the paragraphs [1] to

[68] , or its pharmaceutical salt.

[0310]

[71] w is -nhch 3 , Or -n (ch) 3 ) 2 The compound described in the paragraph

[70] , or its pharmaceutically acceptable salt.

[0311]

[72] The compound described in one of the paragraphs [1] to

[68] , which is an amide that is arbitrarily replaced, or its pharmaceutical salt.

[0312]

[73] W [Formation] The compound described in the paragraph

[72] , or its pharmaceutically acceptable salt.

[0313]

[74] W is arbitrarily replaced c 1 -C 4 The compounds described in one of the alcoholic paragraphs [1] to

[68] , or their pharmaceutical salt.

[0314]

[75] The compound described in paragraph

[74] , which is a metoxy or isopro poxy, or its pharmaceutical salt.

[0315]

[76] W is arbitrarily replaced c 1 -C 4 The compound described in one of the alkyl, paragraphs [1] to

[68] , or their pharmaceutical salt.

[0316]

[77] W is a compound described in methyl, ethyl, isopropyl, tert-butyl, or benzyl, paragraph

[76] , or its pharmaceutical salt.

[0317]

[78] W is arbitrarily replaced c 1 -C 4 The compounds described in one of the hydroxyal kill, paragraph [1] to

[68] , or their pharmaceutical salt.

[0318]

[79] W [Formation] The compound described in the paragraph

[78] , or its pharmaceutically acceptable salt.

[0319]

[80] W is arbitrarily replaced c 1 -C 4 The compound described in one of the amino alkyl, paragraphs [1] to

[68] , or their pharmaceutical salt.

[0320]

[81] W [Formation] The compound described in the paragraph

[80] , or its pharmaceutically acceptable salt.

[0321]

[82] W is arbitrarily replaced c 1 -C 4 The compound described in one of the paragraphs [1] to

[68] , which is a halo alkyl, or its pharmaceutical salt.

[0322]

[83] W [Formation] The compound described in the paragraph

[82] , or its pharmaceutically acceptable salt.

[0323]

[84] W is arbitrarily replaced c 1 -C 4 The compounds described in one of the guanidino alkyl, paragraphs [1] to

[68] , or their pharmaceutical salt.

[0324]

[85] W [Formation] The compound described in the paragraph

[84] , or its pharmaceutically acceptable salt.

[0325]

[86] W is C 0 -C 4 Alkyl, the compounds described in one of the paragraphs [1] to

[68] , which are heterocycloalkyl, which are arbitrarily replaced, or the pharmaceutical salt.

[0326]

[87] W [Formation] [Formation] [Formation] [Formation] [Formation] The compound described in the paragraph

[86] , or its pharmaceutically acceptable salt.

[0327]

[88] W is a compound described in one of the paragraphs [1] to

[68] , which is a cycloalual kill for 3 to 8 members, or its pharmaceutical salt.

[0328]

[89] W [Formation] The compound described in the paragraph

[88] , or its pharmaceutically acceptable salt.

[0329]

[90] W is a compound described in one of the paragraphs [1] to

[68] , which is an arbitrarily replaced heteroaryl, or a pharmaceutical salt.

[0330]

[91] W [Formation] The compound described in the paragraph

[90] , or its pharmaceutically acceptable salt.

[0331]

[92] A compound described in one of the paragraphs [1] to

[68] , which is an aryl of 6 to 10 members that is arbitrarily replaced, or its pharmaceutical salt.

[0332]

[93] W is a compound described in the paragraph

[92] , a paragraph

[92] , or its pharmaceutical salt, or a pharmaceutical salt, which is a phenyl, 4-hydroxy-phenyl, 2,4-metoxy-phenyl.

[0333]

[94] Compounds described in Table 1 or 2, or their pharmaceutical salt.

[0334]

[95] Pharmaceutical composition containing one of the paragraphs [1] to

[94] , or a pharmaceutical salt, and a pharmaceutical -tolerant.

[0335]

[96] In the subject that requires cancer treatment, the above method is one of the above -mentioned paragraphs [1] to

[94] , which is effective for treatment.The above method, including the compounds described in the tip, or the pharmaceutical salt, or the pharmaceutical composition described in paragraphs

[95] .

[0336]

[97] The method described in the paragraph

[96] , which is a paragraph

[96] , is the above cancer, columnar cancer, non -small cell lung cancer, gastric cancer, esophageal cancer, ovarized, or uterine cancer.

[0337]

[98] The method described in the paragraph

[97] , which contains RAS mutation.

[0338]

[99] The method according to the paragraph

[98] , which is in the position 12, 13, or 61.

[0339]

[0100] The above RAS mutation is a paragraph that is K-RAS G12C, K-RAS G12D, K-RAS G12V, K-RAS G12S, K-Ras G13C, K-Ras G13D, or K-RAS Q61L

[98] The method described in.

[0340]

[0101] It is a necessary subject treatment method for the treatment of RAS protein -related diseases.The above method, including the compounds described in one of one, or the pharmaceutical compositions in the paragraph

[95] .

[0341]

[0102] This is an inhibitory method of RAS protein in cells, and the above method is a compound described in one of the above -mentioned cells, a paragraph [1] to

[94] , which is effective for treatment.The above method, which includes the pharmaceutical salt or pharmaceutical compositions described in the paragraph

[95] .

[0342]

[0103] The above RAS proteins are K-RAS G12C, K-RAS G12D, K-RAS G12V, K-RAS G12S, K-Ras G13C, K-Ras G13D, or K-RAS Q61L.Or the method described in

[0102] .

[0343]

[0104] The method described in paragraph

[0102] or

[0103] , which is the above cells.

[0344]

[0105] The method of cancer cells described in paragraphs

[0104] , which is the above -mentioned cancer cells, colon rectal cancer cells, non -small cell pulmonary cells, gastric cancer cells, esophageal cancer cells, or uterine cancer cells, or uterine cancer cells.

[0345]

[0106] The above method includes or used in one of paragraphs

[96] to

[0105] , which includes additional administration of additional anticancer treatment.

[0346]

[0107] The additional anticancer treatments are EGFR inhibitors, second RAS inhibitors, SHP2 inhibitors, SOS1 inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, PTEN inhibitors.AKT inhibitor, Mtorc1 inhibitor, Braf inhibitor, PD-L1 inhibitor, PD-1 inhibitor, CDK4 / 6 inhibitor, HER2 inhibitor, or these combinations, paragraphs

[0106] Method.

[0347]

[0108] The method described in paragraphs

[0106] or

[0107] , which is the SHP2 inhibitor, which is an additional anticancer treatment.

[0348] Example The present disclosure is further exemplified by the following embodiments and composition examples, and should not be regarded as limited to the specific procedure described in the present note described in the present note.It is understood that the embodiment is provided to show specific embodiments, and that no restrictions on the scope of the present disclosure are intended.In addition, there are various other embodiments, modifications, and the equivalents that can be suggested by the art of the art, without deviating from the purpose of the present disclosure or the attached patent claim.I want to understand.

[0349] Chemical synthesis The definitions used in the following embodiment and other locations in the current note are as follows. Ch 2 CL 2 , DCM: methylene chloride, dichloromethane Ch 3 CN, MECN: acetonitrile CUI: Copper -chopped (i) DIPEA: Jisopopyl ethylamine DMF: N, N-dimethylholmamide ETOAC: ethyl acetate H: time H 2 O: Water HCL: Hydrochloric acid K 3 PO 4 : Potassium phosphate (three -state base acid) Meoh: methanol NA 2 So 4 : Sodium sulfate NMP: n-methyl Pyrringon PD (DPPF) CL 2 : [1,1'-bis (diphenylphosfino) Ferosen] dichloro palladium (II)

[0350] Equipment The mass-specific data collection was performed by SHIMADZU LCMS-2020, Agilent 1260LC-6120 / 6125MSD, SHIMADZU LCMS-2010EV, or Waters Acquity Uplc with either QDA detector or SQ detector 2.The sample was injected into the C18 reverse phase by the liquid phase.Using an acetonitrile gradient, a compound was eluted from the column and supplied to a mass spectromer.Initial data analysis was performed in either Agilent Chemstation, Shimadzu LabSolutions, or Waters Masslynx.The NMR data was collected using either BRUKER AVANCE III III HD 400MHz, Bruker Assend 500MHz, or Varian 400MHz, and raw data was analyzed using either Topspin or Mestrelab Mnova.

[0351] Intermediate synthesis Intermediate body 1.3- (5-bromo-1-ethyl-2- [2- [(1s) -1S) -1-metoxyethyl] pyridine-3-Il] Indole -3-Il) -2,2-Dimethyl propane-1-all synthesis [Formation]

[0352] Step 1.N 2 Under the atmosphere, at 0 ° C, 3- (((TERT-Butyl Jphenyl Syrille) oxy) -2,2-2,2-DCM (120ml) of DCM (120ml) of DCM (65g, 137 mmol, rough), 1m.SNCL 4 DCM (137ml, 137 mmol) was slowly added.After the mixture was stirred at 0 ° C for 30 minutes, a DCM (40 ml) solution of 5-bromo-1H-indole (26.8g, 137 mmol) was added.After stirring the mixture at 0 ° C for 45 minutes, diluted it with ETOAC (300ml), washed with brine (100ml x 4), and NA. 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, 1- (5-bromo-1H-indole-3-ol) -3- ((TERT-butyl jefenyl cylyl) oxy) -2, 2, 22-Dimethylopan-1-on (55g, 75%yield) was obtained.LCMS (ESI): m / z [m+na] c 29 H 32 Brno 2 Calculator for sINA, 556.1; actual measured value, 556.3.

[0353] Step 2.N 2 Under the atmosphere of 0 ° C, 1- (5-bromo-1H-Indole-3-Il) -3- (((TERT-butyl jet phenylsyril) oxy) -2,2-dimethyl propane-1-on (50g, 50g,In a mixture with THF (100ml) of 93.6 mmol), libh 4 (6.1g, 281 mmol) was added.After heating the mixture to 60 ° C, stirring for 20 hours, adding meoh (10ml) and ETOAC, cleaning the mixture with brine (50 ml), and NA. 2 So 4 It was dried and filtered, and the film was concentrated under reduced pressure.The residue is diluted with DCM (50 ml), cooled to 10 ° C, jillzine (9.5g, 37.4 mmol) and TSOH · h. 2 O (890 mg, 4.7 mmol) was added.The mixture is stirred at 10 ° C for 2 hours to filter, the filter is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, and 1- (5-bromo-1H-indole-3-Il) -3-.((TERT-Butyl Jefenyl Syril) Oxy) -2,2-Dimethyl propane-1-on (41g, 84%yield).LCMS (ESI): M / Z [M+H] C 29 H 34 Calculation value for brnosi: 519.2; Active value: 520.1; 1 H NMR (400MHz, CDCL 3 δ 7.96 (S, 1h), 7.75-7.68 (m, 5h), 7.46-7.35 (m, 6h), 7.23-7.19 (m, 2h), 6.87 (d, j = 2.1 hz, 1h), 3.40 (3.40 (S, 2h), 2.72 (S, 2H), 1.14 (S, 9H), 0.89 (S, 6H).

[0354] Step 3.1- (5-Bromo-1H-Indole-3-Il) -3- ((TERT-Butyl Jefenylsyil) Oxy) -2,2-Dimethyl Propane-1-on (1.5g, 2.9mmol),And I 2 Agotf (888 mg, 3.5 mmol) was added at room temperature to a mixture (731 mg, 2.9 mmol) with THF (15ml).After stirring the mixture at room temperature for 2 hours, diluted it with eTOAC (200 ml) and saturated NA. 2 S 2 O 3 Clean with (100ml) and anhydride NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, 5-bromo-3- (((TERT-butt-butyl jet phenylsyril) oxy) -2,2-dimethyl propyl) -2-.Ido-1H-Indole (900mg, 72%yield) was obtained as a solid. 1 H NMR (400MHz, DMSO-D 6 δ 11.70 (S, 1h), 7.68 (D, J = 1.3 Hz, 1h), 7.64-7.62 (m, 4H), 7.46-7.43 (m, 6H), 7.24-7.22 (D, 1h), 7.14-7.12 (DD, J = 8.6, 1.6 Hz, 1h), 3.48 (S, 2H), 2.63 (S, 2H), 1.08 (S, 9H), 0.88 (S, 6H).

[0355] Step 4.Under the atmosphere of AR, at 0 ° C, the mixture of HCOOH (66.3g, 1.44 mol) with TEA (728 mg, 7.2 mol), (4S, 5s) -2-chloro-2-methyl-1- (4-Methylbenzenzenil) -4,5-Ziphenyl-1,3-Giaza-2-Lutenasclopentan Simen (3.9g, 6.0 mmol) was added in several parts.The mixture was heated to 40 ° C and stirred for 15 minutes, then cooled to room temperature, and 1- (3-bromopyridine-2-Il) ethanon (120g, 600 mmol) was added in small parts.The mixture was heated to 40 ° C, stirred for 2 hours, and the solvent was concentrated under reduced pressure.Add brine (2L) to the residue, extract a mixture with eTOAC (4x700ml), anhydrous NA. 2 So 4It was dried and filtered.The film was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and (1S) -1- (3-bromopyridine-2-Il) ethanol (100g, 74%yield) was obtained as oil.LCMS (ESI): M / Z [M+H] C 7 H 8 Calculator for BRNO: 201.1; Actual measured value 201.9.

[0356] NAH (60%distributed solution of oil) in the stirring mixture of (1S) -1- (3-bromopyridine-2-Il) ethanol (100g, 495 mmol) DMF (1L) at (1S) -1- (3-bromopyridine-2-Il).14.25g, 594 mmol) was added in small parts.The mixture was stirred at 0 ° C for 1 hour.MEI (140.5g, 990 mmol) was added at 0 ° C, the mixture was heated to room temperature, and the mixture was stirred for 2 hours.Cool the mixture to 0 ° C and saturate NH 4 CL (5L) was added.Extract the mixture with ETOAC (3 × 1.5L), anhydrous NA 2 So 4 It was dried and filtered.The film was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 3-bromo-2- [(1s) -1-metoxyethyl] pyridine (90g, 75%yield) was obtained as oil.LCMS (ESI): M / Z [M+H] C 8 H 10 Calculation value for BRNO: 215.0; Active value 215.9.

[0357] Step 6.Under the atmosphere of AR, at room temperature, 3-bromo-2- [(1s) -1-metoxyethyl] pyridine (90g, 417 mmol) and PD (DPPF) CL 2 (30.5g, 41.7 mmol), a stirring mixture with toluene (900 ml) was added in a small division of bis (127g, 500 mmol) and KOAC (81.8g, 833 mmol).The mixture was heated to 100 ° C and stirred for 3 hours.Concentrate the film under reduced pressure and the residue is AL. 2 O 3 Refined by column chromatography, 2- [(1s) -1-metoxyethyl] -3- (4,4,5,5-tetramethyl-1,3,2-gexabolan-2-Il) pyridine (100g, 100g,63%yield) was obtained as a semi -solid.LCMS (ESI): M / Z [M+H] C 14 H 22 Bno 3 Calculator for: 263.2; Active value 264.1.

[0358] Step 7. 5-Bromo-3- [3- [(TERT-butyl jet phenylsyril) oxy] -2,2-dimethyl propyl] -2-iode-1H-indole (140g, 217 mmol) and 2- [(1s)-1-Methoxyethyl] -3- (4,4,5,5-tetramethyl-1,3,2-geoxabolan-2-Il) pyridine (100g, 380mmol), 1,4-geoxan (1.4L)In the stirring mixture with, under the atmosphere of AR, at room temperature, K. 2 Co 3 (74.8g, 541mmol), PD (DPPF) CL 2 (15.9g, 21.7mmol), and H 2 O (280ml) was subdivided and added.Heat the mixture to 85 ° C, stir for 4 hours and cool, and H. 2 O (5L) was added and a mixture was extracted with ETOAC (3x2L).Clean the combined organic layer with brine (2x1L), anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, 5-bromo-3- [3- [(TERT-butt-butyl zlyphenylsyril) oxy] -2,2-dimethyl propille] -2- [.2- [(1s) -1-Methoxyethyl] Pyridine-3-Il] -1H-Indole (71g, 45%yield) was obtained as a solid.LCMS (ESI): M / Z [M+H] C 37 H 43 Brn 2 O 2 Calculator for SI: 654.2; Active value 655.1.

[0359] Step 8.N 2 Under the atmosphere of 0 ° C, 5-bromo-3- [3- [(TERT-butyl jet phenylsyril) oxy] -2,2-dimethyl propyl] -2- [(1s) -1-metoxyethyl] Pyridine-3-Il] -1H-Indole (71g, 108mmol), a stirring mixture with DMF (0.8L), CS 2 Co 3 (70.6g, 217 mmol) and ETI (33.8g, 217 mmol) were subdivided and added.After heating the mixture to room temperature, stirring for 16 hours, H 2 O (4L) was added and a mixture was extracted with ETOAC (3 × 1.5L).Clean the combined organic layer with brine (2x1L), anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, 5-bromo-3- [3- [(TERT-butyl jet phenylsilyl) oxy] -2,2-dimethyl propyl] -1-.Ethyl-2- [2- [(1s) -1-Methoxyethyl] Pyridine-3-Il] Indole (66g, 80%yield) was obtained as oil.LCMS (ESI): M / Z [M+H] C 39 H 47 Brn 2 O 2 Calculator for SI: 682.3; Active value 683.3.

[0360] Step 9.N 2 Under the atmosphere of the room, at room temperature, the stirring mixture of TBAF (172.6g, 660 mmol) with THF (660ml), 5-bromo-3- [3- [(TERT-butt-butyl jet phenylsyril) oxy] -2,2--Dimethyl Propil] -1-ethyl-2- [2- [2- [(1s) -1S) -1-Methoxyethyl] pyridine-3-Il] Indole (66g, 97mmol) was added in small part.Heat the mixture to 50 ° C, stir for 16 hours, cool, and H. 2 It was diluted with o (5L) and extracted with ETOAC (3 × 1.5L).Clean the combined organic layer with brine (2x1L), anhydrous NA 2 So 4 It was dried and filtered.After filtration, the film was concentrated under reduced pressure.The film is concentrated under reduced pressure, the residue is purified by silica gel column chromatography to 3- (5-bromo-1-ethyl-2- [2- [(1s) -1s) -1-metoxyethyl] pyridine-3-.Il] Indole -3-Il) -2,2-dimethyl propane-1-all (30g, 62%yield) was obtained as a solid.LCMS (ESI): M / Z [M+H] C 23 H 29 Brn 2 O 2 Calculator for: 444.1; Active value 445.1.

[0361] Intermediate body 1.An alternative synthesis by the Fisher Indoor route.

[0362] [Formation]

[0363] Step 1: n 2 Under the atmosphere of -10 ° C, N-BULI (2.5m, 333 ml, 833 mmol) was added to the I-PRMGCL mixture (2m, in THF, 0.5L) for 15 minutes.After stirring the mixture at -10 ° C for 30 minutes, the solution of 3-bromo-2- [(1s) -1-metoxyethyl] pyridine (180g, 833 mmol) of THF (0.5L) is -10 ° C. for 30 minutes.I added it.After warming the obtained mixture to -5 ° C, stirring for 1 hour, the solution of 3,3-dimethyl oxan-2,6-zeon (118g, 833 mmol) THF (1.2L) solution is -5 ° C for 30 minutes.I added it.The mixture was heated to 0 ° C, and after stirring for 1.5 hours, the HCL in the 4m pool in advance was added at 0 ° C and the pH was adjusted to about 5.The mixture was diluted with ice water (3L) and extracted with ETOAC (3 × 2.5L).Anhydride NA is the combined organic layer 2 So 4 Dry, filter, concentrate the film under reduced pressure, purify the residue with silica gel column chromatography, and 5- [2- [(1s) -1-metoxyethyl] pyridine-3-Il] -2., 2-dimethyl-5-oxopentanic acid (87g, 34%yield) was obtained as a solid.LCMS (ESI): M / Z [M+H] C 15 H 21 NO 4 Calculator for: 279.2; Active value 280.1.

[0364] Step 2.N 2 Under the atmosphere, at room temperature, 5- [2- [(1s) -1-metoxyethyl] pyridine-3-Il] -2,2,2-5-oxopentanic acid (78g, 279 mmol), etoh (0.78)(4-bromofenyl) hydrazine hydrochloride (68.7 g, 307 mmol) was added to the mixture with L).The mixture was heated to 85 ° C and stirred for 2 hours, and after cooling to room temperature, a 4m HCL (69.8 ml, 279 mmol) was added.The mixture was heated to 85 ° C, stirred for another 3 hours, then concentrated under reduced pressure, and the residue was dissolved in TFA (0.78L).Heat the mixture to 60 ° C, stir 1.5, concentrate under reduced pressure, and saturate NAHCO. 3 After adjusting the pH of the residue to about 5, it was extracted with ETOAC (3 × 1.5L).Anhydride NA is the combined organic layer 2 So 4Dry and filter, concentrate the film under reduced pressure, purify the residue with silica gel column chromatography to 3- (5-bromo-2- [2- [(1s) -1S) -1-metoxierethyl] pyridin.-3- Il] -1H-Indole-3-Il) -2,2-Dimethylopolic acid and ethyl (S) -3- (5-bromo-2- (2- (1-metoxyethyl) pyridine -3-Il) -1H-Indole-3-Il) -2,2-2,2-Dimethylpropanaate (78g, rough).LCMS (ESI): M / Z [M+H] C 21 H 23 Brn 2 O 3 Calculated value: 430.1, and c 23 H 27 Brn 2 O 3 Calculator: 458.1; Active value 431.1 and 459.1.

[0365] Step 3.N 2 Under the atmosphere of 0 ° C, 3- (5-bromo-2- [2- [(1s) -1S) -1-metoxyethyl] pyridine-3-Il] -1H-Indole-3-Il) -2,2, 2,2-Dimethyl propepid acid and ethyl (S) -3- (5-bromo-2- (2- (1-metoxyethyl) pyridine -3-Il) -1H-Indole-3-Il) -2,2,2,2,2-2-CS for a mixture with DMF (1.8L) of an ane (198g, 459 mmol) 2 Co 3 (449g, 1.38 mol) was added in small parts.Next, a DMF (200ml) solution of ETI (215g, 1.38 mmol) was added at 0 ° C.The mixture was heated to room temperature, stirred for 4 hours, diluted with brine (5L), and extracted with ETOAC (3x2.5L).Clean the combined organic layer with brine (2 × 1.5L), anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography to ethyl 3- (5-bromo-1-ethyl-2- [2- [(1s) -1s) -1-metoxyethyl] pyridine -3.-Il] Indole -3-Il) -2,2-Dimethylpropanaate (160g, 57%yield) was obtained as a solid.LCMS (ESI): M / Z [M+H] C 25 H 31 Brn 2 O 3 Calculator for: 486.2; Active value 487.2.

[0366] Step 4.N 2 Under the atmosphere of 0 ° C, ethyl 3- (5-bromo-1-ethyl-2- [2- [2- [(1s) -1s) -1S) -3-ilidine-3-ol] Indole-3-Il) -2, 2, 2,2-For a mixture of THF (1.6L) of the dimethyl propanogates (160g, 328 mmol), libh 4 (28.6g, 1.3 mol) was added.The mixture was heated to 60 ° C for 16 hours, cooled, and pooled in advance (0 ° C) nh 4 I quenched with a CL aqueous solution (5L).Extract the mixture with ETOAC (3x2L), wash the combined organic layer with brine (2x1L), anhydrous NA. 2 So 4 It was dried and filtered.The film is concentrated under reduced pressure, the residue is purified by silica gel column chromatography to 3- (5-bromo-1-ethyl-2- (2- (S) -1-metoxyethyl) pyridine-3-.Il) -1H-Indole-3-Il) -2,2, 2,2-Dimethyl propane-1-All atrop anetoproeters (as a single atrop anetometary) (60g, 38%yield, and 40 g, 26%The yield) was obtained as a solid.LCMS (ESI) M / Z: [M+H] C 23 H 29 Brn 2 O 2 Calculator for: 444.1; Active value 445.2.

[0367] Intermediate 2 and intermediate 4.(S) -1- ((s) -2- ((TERT-butoxycalbonil) Amino) Amino) -3- (3- (4,4,5,5-Tetramethyl-1,3,2-Gexaboran-2-Il) -5- ((Triisopyl Cyril) Oxy) Phenyl) Proponoy) Hexhadropyridadin-3-Carboxylate synthesis [Formation]

[0368] Step 1.(S) -Methyl 2- (TERT-Butoxycal Bonylamino) -3- (3-Hydroki Schiphenyl) propanote (10.0g, 33.9 mmol), a mixture with DCM (100 ml), imidazole (4.6g, 67.8 mmol)And tipsCl (7.8g, 40.7 mmol) was added.After stirring the mixture at room temperature overnight, diluted it with DCM (200 ml) and H. 2 Washed with O (150ml x 3).Oils of organic layers na 2 So 4 Dry and filter, concentrate under reduced pressure, purify the residue with silica gel column chromatography, and (S) -methyl 2- (TERT-butoxicurbonylamino) -3- (3-)) Phenyl)-Propanote (15.0g, 98%yield) was obtained as oil.LCMS (ESI): m / z [m+na] c 24 H 41 NO 5 Calculation value for sINA: 474.3; Active value 474.2.

[0369] Step 2.(S) -Methyl 2- (TERT-Butoxycal Bonylamino) -3- (3- (3- (Trisopyl Cyriloxy) Phenyl)-Propanote (7.5g, 16.6mmol), Pinb 2 (6.3g, 24.9mmol), [IR (OME) (COD)] 2 (1.1g, 1.7 mmol), and 4-Tert-butyl-2- (4-Tert-butyl-2-pyridyl) pyridine (1.3g, 5.0 mmol) with AR (× 3), THF(75ml) was added, and the mixture was placed under the atmosphere of AR.The mixture is heated to 80 ° C, stirring for 16 hours, concentrated under reduced pressure, the residue is purified by silica gel column chromatography, (S) -Methyl 2- (TERT-butoxical Bonylamino) -3- (3-(4,4,5,5-5-Tetramethyl-1,3,2-Gexabolan-2-Il) -5- (Trisopyl Cylilly Liloxy) Phenyl) -Prupano Eate (7.5g, 78%yield) is a solid.Obtained.LCMS (ESI): m / z [m+na] c 30 H 52 Bno 7 Calculator for sINA: 600.4; Active value 600.4; 1 H NMR (300MHz, CD3OD) Δ 7.18 (S, 1h), 7.11 (S, 1h), 6.85 (S, 1H), 4.34 (M, 1h), 3.68 (S, 3H), 3.08 (M, 1h),2.86 (m, 1h), 1.41-1.20 (m, 26h), 1.20-1.01 (m, 22H), 0.98-0.79 (m, 4H).

[0370] Step 3.0 ° C, Triisopyl Cyril (S) -2- ((TERT-butoxycalbonyl) Amino) -3- (3- (4,4,5,5-Tetramethyl-1,3,2-Gexabolan)-2-Il) -5- ((Triisopyl Syril) Oxy) Phenyl) Propanote (4.95g, 6.9 mmol), a mixture with MEOH (53 ml), a water solution (35 ml) of LIOH (840 mg, 34.4 mmol).Added.After stirring the mixture at 0 ° C for 2 hours, it was acidified with 1m HCL, pH was set to about 5, and extracted with ETOAC (250ml x 2).Clean the combined organic layer with brine (100ml x 3), anhydrous NA 2 So 4 Dry and filter, concentrate the film under reduced pressure, (S) -2- (((Tert-butoxycarbonyl) amino) amino) -3- (3- (4,4,5,5-Tetramethyl-).1,3,2-Gexabolan-2-Il) -5- ((Trisopyl Cyril) Oxy) phenyl acid (3.7 g, 95%yield)used.LCMS (ESI): M / Z [M+NH 4 ] C 29 H 50 Bno 7 Sinh 4 Calculated to: 581.4; Active value 581.4.

[0371] At 4.0 ° C., Methyl (S) -Hexahydropyridadin-3-Carboxylate (6.48g, 45.0 mmol), a mixture with DCM (200 ml), NMM (41.0g, 405mmol), (S)-2- ((TERT-Butoxycal Bonil) Amino) -3- (3- (4,4,5,5-Tetramethyl-1,3,2-Gexabolan-2-Il) -5-Oxy) Phenyl) Properic acid (24g, 42.6 mmol) DCM (50 ml) solution, followed by Hobt (1.21g, 9.0 mmol) and EDCI hydrochloride (12.9g, 67.6 mmol).After warming the mixture to room temperature and stirring for 16 hours, diluted it with DCM (200 ml) and H. 2 Washed with O (3 x 150ml).Oils of organic layers na 2 Dry it with SO and filter, concentrate the filter solution under reduced pressure, purify the residue with silica gel column chromatography, to methyl (S) -1- (S) -2- ((TERT-butoxycarbonil) amino).) -3- (3- (4,4,5,5-5-tetramethyl-1,3,2-geoxabolan-2-ol) -5- ((Triisopyl Cyril) Oxy) Fenyil) Hexahidropyridazine-3-Carboxylate (22g, 71%yield) was obtained as oil.LCMS (ESI): M / Z [M+H] C35 H 60 Bn 3 O 8 Calculator for SI: 689.4; Active value 690.5.

[0372] Intermediate body 3.(S) -TERT-butyl 3-methyl-2- ((s) -n-methyl pyrringine -3-carboxamide) synthesis [Formation]

[0373] Step 1.In the room temperature, (S) -1- (TERT-butoxycarbonil) Pyrringon-3-carboxylic acid (2.2g, 10.2 mmol), a mixture with DMF (10ml), HATU (7.8 g, 20.4 mmol) and DIPEA (DIPEA (DIPEA).5ml) was added.After stirring at room temperature for 10 minutes, a DMF (10 ml) solution of TERT-Butylmethyl-L-Varine (3.8g, 20.4 mmol) was added.After stirring the mixture at room temperature for 3 hours, DCM (40ml) and H. 2 I diluted it with o (30ml).Separate the water layer and the organic layer to H in the organic layer 2 O (3x30ml), wash with brine (30ml), anhydrous NA 2 So 4 It was dried and filtered.Concentrate the filter solution under reduced pressure, purify the residue with silica gel column chromatography, and (s) -tert-butyl 3- (((s) -1- (TERT-butoxy)) -3-methyl-1-oxobutan.-2-Il) (Methyl) Calva Mile) Pyrolidon-1-Carboxilate (3.2g, 82%yield) was obtained as oil.LCMS (ESI): m / z [m+na] c 20 H 36 N 2 O 5 Calculator for NA: 407.3; Active value 407.2.

[0374] Step 2.(S) -Tert-butyl 3- (((S) -1- (TERT-butoxy)) -3-methyl-1-oxobutan-2-Il) (methyl) Calva mile) Pyrolidon-1-Carboxilate (3.2g,A mixture of 8.4 mmol) between DCM (13ml) and TFA (1.05g, 9.2 mmol) was stirred at room temperature for 5 hours.Concentrate the mixture under reduced pressure, (S) -Tert-butyl 3-methyl-2- ((s) -n-metile pyrryidine-3-carboxamide) button (2.0g, 84%yield) is obtained as oil.rice field.LCMS (ESI) M / Z: [M+H] C 15 H 28 N 2 O 3 Calculator for: 284.2; Active value 285.2.

[0375] Intermediate 5.TERT-Butyl ((6) 3S ,Four S ) -1 1 -Etile-1 2 -(2- S ) -1-Metoxyethyl) Pyridine-3-Il) -10,10-dimethyl-5,7-geoxo-2 5 -((Triisopyl Syril) Oxy) -6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-11H-8-Oxa-1 (5,3)-Indra-6 (1,3) -Pyridazina-2 (1,3) -Benzenasicrowon Dekaffan-4-Il) Calvamate.

[0376] [Formation] Step 1.3- (5-bromo-1-ethyl-2- [2- [(1s) -1S) -1-metoxyethyl] pyridine-3-Il] Indole-3-Il) -2,2,2-Methyl propane-1-all (30g, 67 mmol) and methyl (3s) -1- [(2s) -2- [(TERT-butoxycal bonil) Amino] -3- [3- [4,4,5, 5,5-Tetramethyl-1,3,2-Gexabolan-2-Il) -5- [(Trisopyl Cyril) Oxye] Propanile] -1,2-Giazinan -3-Carboxylate (55.8g, 80.8mmol)In the stirring mixture of 1,4-geoxan (750 ml), NA 2 Co 3 (17.9g, 168.4mmol), PD (DTBPF) CL 2 (4.39g, 6.7mmol), and H 2 O (150.00ml) was subdivided and added.Heat the mixture to 85 ° C, stir for 3 hours, cool, and H. 2 It was diluted with o (2L) and extracted with ETOAC (3x1L).Clean the combined organic layer with brine (2 x 500ml), anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, methyl (3s) -1- [(2s) -2- [(TERT-butoxycalbonyl) amino] -3- [3- [3- [3- [3- [1-ethyl-3- (3-hydroxy-2,2-dimethyl propyl) -2- [2- [(1s) -1-1S) -1-metoxyethyl] pyridine-3-Il] Indole-5- [(Triisopyl Cyril) Oxy] Phenyl] Proponoyl] -1,2-Giazinan -3-Carboxylate (50g, 72%yield) was obtained as a solid.LCMS (ESI): M / Z [M+H] C 52 H 77 N 5 O 8 Calculator for Si: 927.6; Active value 928.8.

[0377] Step 2.At room temperature, methyl (3s) -1- [(2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [1-ethyl-3- (3-hydroxy-2,2-dimethyl propyl)) -2- [2- [(1s) -1S) -1-Metoxyethyl] Pyridine-3-Il] Indole-5-Il] -5- [(Trisopyl Cyril) Oxy] Phenyl] -1,2-Giazinan-3-Carboxylate (50g, 54 mmol), a stirring mixture with DCE (500 ml), was added in a subdivision of trimethyl hydroxide (48.7g, 269 mmol).The mixture was heated to 65 ° C, stirred for 16 hours, then filtered, and the filter mass was washed with DCM (3 × 150 ml).Concentrate the filter solution under reduced pressure, (3s) -1- [(2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [1-ethyl-3- (3- Hydroxy-2), 2-dimethyl propyl) -2- [2- [(1s) -1-metoxyethyl] pyridine-3-Il] Indole-5-Il] -5- [(Triisopyl Cyril) Oxye] Proponoy1,2-Giazinan -3-carboxylic acid (70g, rough) was obtained, and it was used directly in the next step without further purification.LCMS (ESI): M / Z: [M+H] C 51 H 75 N 5 O 8 Calculator for SI: 913.5; Active value 914.6.

[0378] Step 3.N 2 Under the atmosphere of 0 ° C, (3s) -1- [(2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [1-ethyl-3- (3- Hydroxy-2, 2, 2, 2, 2,2-dimethyl propyl) -2- [2- [(1s) -1-metoxyethyl] pyridine-3-Il] Indole-5-Il] -5- [(Triisopyl Cyril) Oxye] Propoil] -1, 2-Ziazinan -3-Carboxylic acid (70g), divide the stirring mixture with DCM (5L) to DIPEA (297g, 2.3 mol), Hobt (51.7g, 383 mmol), and EDCI (411g, 2.1 mol).In addition, it was added.After warming the mixture to room temperature and stirring for 16 hours, diluted it with DCM (1L), washed with brine (3x1L), anhydrous NA. 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography to TERT-butyl ((6). 3 S, 4s) -1 1 -Etile-1 2 -(2- ((s) -1-Metoxyethyl) pyridine-3-Il) -10,10-dimethyl-5,7-geoxo-2 5 -((Triisopyl Syril) Oxy) -6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-1 (5,3)-Indra-6 (1,3) -Pyridazina-2 (1,3) -Benzenasicrow de Cafan-4-Il) Calvamate (36g, 42%yield) Won as a solid.LCMS (ESI): M / Z [M+H] C 51 H 73 N 5 O 7 Calculator for SI: 895.5; Active value 896.5.

[0379] Intermediate 6.TERT-Butyl N- [(8s, 14s) -21-iodine-18,18-Dimethyl-9,15-Geoxo-4- [(Trisopyl Cyril) Oxy] -16-Oxa -10,22,28-TriaZapenta Sicro [18.5.2.1^[2,6] .1^[10,14] .0^[23,27]] Nonakosa-1 (26), 2,4,6 (29), 20,23 (29)27), 24-Heptaen-8-Il] Calvamate synthesis. [Formation]

[0380] Step 1.The reaction was performed in five batches, in parallel on the scales described below.

[0381] 5-bromo-3- [(TERT-butt-butyl Jphenylsyil) oxy] -2,2-dimethyl propille] -1H-indole (100g, 192mmol) and TBAF (301.4G, 301.4G, 301.4g, 301.4G, 301.4G, 301.4G,1.15 mol) THF (1.15L) solution was added at room temperature.The obtained mixture was heated to 50 ° C, stirred for 16 hours, and then concentrated under reduced pressure.The combined residue is H 2 It was diluted with o (5L) and extracted with ETOAC (3x2L).Clean the combined organic layer with brine (2 × 1.5L), anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, and 3- (5-bromo-1H-indole-3-Il) -2,2-dimethyl propane-1-all (310g, roughly rough.) Won as a solid.LCMS (ESI): M / Z [M+H] C 13 H 16 Calculated value for BRNO: 281.0 and 283.0; Active value 282.1 and 284.1.

[0382] Step 2.The reaction was performed in two batches, in parallel on the scales described below.

[0383] N 2 Under the atmosphere of 0 ° C, 3- (5-bromo-1H-indole-3-Il) -2,2-dimethylopan-1-all (135g, 478 mmol) and TEA (145.2g, 1.44 mol),AC for the stirring mixture with DCM (1.3L) 2 O (73.3g, 718 mmol) and DMAP (4.68g, 38.3 mmol) were subdivided and added.After stirring the obtained mixture at 0 ° C for 10 minutes, H 2 Washed with O (3x2L).Combined with organic layers from each experiment, wash with brine (2x1L), anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by a column chromatography, and 3- (5-bromo-1H-indole-3-Il) -2,2-dimethyl propyl acetate (304g, 88%yield).Gained as a solid. 1 H NMR (400MHz, DMSO-D 6 δ 11.16-11.11 (m, 1h), 7.69 (d, j = 2.0 hz, 1h), 7.32 (d, j = 8.6 Hz, 1h), 7.19-7.12 (m, 2h), 3.69 (S, 2h), 2.64 (S, 2H), 2.09 (S, 3H), 0.90 (S, 6H).

[0384] Step 3.The reaction was performed in four batches, in parallel on the scales described below.

[0385] In the 2L round bottom flask, under the atmosphere of AR, at room temperature, methyl (2s) -2- [(TERT-butoxycalbonyl) Amino] -3- [3- [4,4,5,5-Tetramethyl-1), 3,2-Gexabolan-2-Il) -5- [(Trisopyl Syril) Oxy] Fenyl] Propanote (125g, 216mmol), 1,4-Geoxan (1L), H 2 O (200ml), 3- (5-bromo-1H-indole-3-Il) -2,2-dimethyl propilla acetate (73.7g, 227 mmol), k 2 Co 3 (59.8g, 433 mmol), and PD (dtbpf) CL 2 (7.05g, 10.8 mmol) was added.After heating the obtained mixture to 65 ° C and stirring for 2 hours, H 2 I diluted it with o (10L) and extracted with ETOAC (3x3L).Clean the combined organic layer with brine (2x2L), anhydrous NA 2 So 4 It was dried and filtered.The film is concentrated under reduced pressure, the residue is purified by a column chromatography to methyl (2s) -3- (3- [3- [acetoxy) -2,2-dimethyl propille] -1H-Indole.-5-Il] -5- [(Trisopyl Syril) Oxy] Fenyl) -2- [(TERT-butoxycarbonyl) Amino] Propanote (500g, 74%yield) was obtained as oil.LCMS (ESI): m / z [m+na] c 39 H 58 N 2 O 7 Calculation value for sINA: 717.4; Active value 717.3.

[0386] Step 4.The reaction was performed in three batches in parallel on the scales described below.

[0387] Methyl (2s) -3- (3- [3- [3- (acetoxy) -2,2-dimethyl propil] -1H-Indole-5-Il] -5- [(Triisopyl Slyl) Oxye] Fenyl)-2- [(TERT-Butoxycal Bonyl) Amino] Propanote (150g, 216mmol) and NAHCO 3 A THF solution of AGOTF (66.5g, 259 mmol) was added to the stirring mixture of (21.76g, 259 mmol) with THF (1.5L) at 0 ° C. under a nitrogen atmosphere.I 2 The THF solution of (49.3g, 194 mmol) was added at 0 ° C for an hour, and the obtained mixture was stirred at 0 ° C for another 10 minutes.Combined experiments, NA 2 S 2 O 3 It was diluted with an aqueous solution (5L) and extracted with ETOAC (3x3L).Clean the combined organic layer with brine (2 × 1.5L), anhydrous NA 2 So 4 It was dried and filtered.The film is concentrated under reduced pressure, the residue is purified by a column chromatography to methyl (2s) -3- (3- [3- [acetyloxy) -2,2-dimethyl propille] -2-.Ido-1H-Indole-5-Il] -5- [(Trisopyl Cyril) Oxy] Phenyl) -2- [(TERT-butoxycarbonil) Amino] Propanote (420g, 71%yield) was obtained as oil.LCMS (ESI): m / z [m+na] c 39 H 57 In 2 O 7 Calculation value for sINA: 843.3; Active value 842.9.

[0388] Step 5.The reaction was performed in three batches in parallel on the scales described below.

[0389] Methyl (2s) -3- (3- [3- [acetyloxy) -2,2-dimethyl propyl] -2-iodo-1H-Indole-Il] -5 in 2L round bottom flask-[(Trisopyl Cyril) Oxy] Phenyl) -2- [(TERT-butoxycalbonil) Amino] Propanote (140g, 171mmol), Meoh (1.4L), and K 3 PO 4 (108.6g, 512 mmol) was added at 0 ° C.After warming the mixture to room temperature and stirring for 1 hour, the combined experimental material H 2 It was diluted with o (9L) and extracted with ETOAC (3x3L).Clean the combined organic layer with brine (2x2L), anhydrous NA 2 So 4 Dry and filter, concentrate the filter solution under reduced pressure, methyl (2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [3- (3- Hydroxy-2,2, 2, 2).-2-iodine-1H-Indole-5-Il] -5- [(Trisopyl Cyril) Oxy] Fenyl] Propanote (438g, rough) was obtained as a solid.LCMS (ESI): m / z [m+na] c 37 H 55 In 2 O 6 Calculation value for sINA: 801.3; Active value 801.6.

[0390] Step 6.The reaction was performed in three batches in parallel on the scales described below.

[0391] Methyl (2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [3- (3- (3- (3- (3- (3- (3-)! 2,2,2, 2,2, 2,2, 2,2, 2,2) -2-dim-5- [(Triisopyl Cyril) Oxy] Phenyl] In the stirring mixture of THF (1.46L) of Propanote (146g, 188 mmol), a water solution (937 ml) of LIOH (22.45g, 937 mmol) is added to 0 ° C.did.The obtained mixture was warmed up to room temperature and stirred for 1.5 hours.The mixture was acidified to pH5 with 1m HCL (1m), and the combined experimental object was extracted with ETOAC (3x3L).Clean the combined organic layer with brine (2x2L), anhydrous NA 2 So 4 Dry and filter, concentrate the filter solution under reduced pressure, (2s) -2- [(Tert-butoxycarbonyl) Amino] -3- [3- [3- (3- Hydroxy-2,2,2-)Dimethyl Propir) -2-iodine-1H-Indole-5-Il] -5- [(Trisopyl Cyril) Oxy] Phenyl acid (402g, rough) was obtained as a solid.LCMS (ESI): m / z [m+na] c 36 H 53 In 2 O 6 Calculation value for sINA: 787.3; Active value 787.6.

[0392] Step 7.(2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [3- (3-hydroxy-2,2-dimethyl propyl) -2-iodine-1H-Indole-Il]-5- [(Trisopyl Syrill) Oxy] Phenylic acid (340g, 445mmol) and methyl (3s) -1,2-Giazinan-3-carboxylate (96.1g, 667 mmol), DCM (3.5L).NMM (225g, 2.2 mol), EDCI (170g, 889 mmol), and HOBT (12.0g, 88.9 mmol) were added to the stirring mixture at 0 ° C.After warming the mixture to room temperature and stirring for 16 hours, H 2 O (3 × 2.5L), wash with brine (2x1L), anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by a column chromatography, methyl (3s) -1- [(2s) -2- [(TERT-butoxycarbonyl) Amino] -3- [3- [3- [3- [3)-(3-hydroxy-2,2-dimethyl propyl) -2-iodine-1H-Indole-5-Il] -5- [(Triisopyl Cyril) Oxy] Fenyl] -1,2-Giaginan -3-Calvoxilate (310g, 62%yield) was obtained as oil.LCMS (ESI): M / Z [M+H] C 42 H 63 In 4 O 7 Calculator for Si: 890.4; Active value 890.8.

[0393] Step 8.The reaction was performed in three batches in parallel on the scales described below.

[0394] N 2 Under the atmosphere of 0 ° C, methyl (3s) -1- [(2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [3- (3- (3- (3- (3-) Hydroxy) -2,2-dimethyl)Propill) -2-iode-1H-Indole-5-Il] -5- [(Trisopyl Cyril) Oxy] Proponoy] -1,2-Giazinan-3-Carboxylate (85.0g, 95.4mmol),The aqueous solution (410 ml) of LIOH (6.85g, 286 mmol) was added to the stirring mixture with the THF (850 ml).The mixture was stirred at 0 ° C for 1.5 hours.。Clean the combined organic layer with brine (2 × 1.5L), anhydrous NA 2 So 4 Dry and filter, concentrate the film under reduced pressure, (3s) -1- [(2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [3- [3- [3)-2, 2,2-dimethyl propyl) -2-iodor-1H-Indole-5-Il] -5- [(Triisopropyl Cyril) Oxy] Fenyl] -1,2-Giazinan-3-Carboxylic acid (carboxylic acid (240g, rough) was obtained as a solid.LCMS (ESI): M / Z [M+H] C 41 H 61 In 4 O 7 Calculator for SI: 876.3; Active value 877.6.

[0395] Step 9.The reaction was performed in two batches, in parallel on the scales described below.

[0396] N 2 Under the atmosphere of 0 ° C, (3s) -1- [(2s) -2- [(TERT-butoxycalbonil) Amino] -3- [3- [3- (3- (3- (3- (3-) Hydroxy) -2,2,2-dimethyl propille)) -2-iodine-1H-Indole-5-Il] -5- [(Trisopyl Cyril) Oxy] Propanile] -1,2-Giazinan -3-Carboxylic acid (120g, 137 mmol), DCM (6L)) DIPEA (265g, 2.05 mol), EDCI (394g, 2.05 mol), and Hobt (37g, 274 mmol) were added to the stirring mixture with).After warming the mixture to room temperature and stirring overnight, the combined experimental material H 2 O (3 × 6L), brine (2x6L), wash with anhydrous NA 2 So 4 It was dried and filtered.After filtration, the film was concentrated under reduced pressure.The filter solution is concentrated under reduced pressure, the residue is purified by a column chromatography to Tert-butyl N- [(8s, 14s) -18,18-Dimethyl-9,15-Zimethyl-4- [.(Triisopyl Cyril) Oxy] -16-Oxa-10,22,28-Tria Penta Cyclo [18.5.2.1^[2,6] .1^[10,14] .0^[23,27]] Nonakosa-1 (26), 2,4,6 (29), 20,23 (27), 24-Heptaen-8-Il] Calvimate (140g, 50%yield) was obtained as a solid.LCMS (ESI): M / Z [M+H] C 41 H 59 In 4 O 6 Calculator for SI: 858.9; Active value 858.3.

[0397] Intermediate body 7.(6 3S , 4s) -4-Amino-1 1 -Etile-2 5 -Hydroxy-1 2 -(4- (metoxymethyl) pyridine-3-Il) -10,10-dimethyl-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-1 (5,3)-Indeal-6 (1,3) --Pyridazina-2 (1,3) --Benzena Sicrounde Cafan-5,7-Synthesis [Formation]

[0398] Step 1.Under the atmosphere of AR, at room temperature, 3-bromo-4- (metoxymethyl) pyridine (1.00g, 5.0mmol), 4,4,5,5-Tetramethyl-2- (Tetramethyl-1,3,2- (Tetramethyl-2-)Gexabolan-2-Il) -1,3,2-Gexabolan (1.51g, 5.9 mmol), and KOAC (1.21g, 12.3 mmol), a mixture with toluene (10 ml), PD (DPPF) CL. 2 (362 mg, 0.5 mmol) was added.Heat the mixture to 110 ° C, stir overnight, then concentrate under reduced pressure, and 4- (metoxymethyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxabolan----.2-Il) I got a pyridine and used it directly in the next process without further purification.LCMS (ESI): M / Z [M+H] C 13 H 20 Bno 3 Calculator for: 249.2; Active value 250.3.

[0399] Step 2.Under the atmosphere of AR, at room temperature, 4- (metoxymethyl) -3- (4,4,5,5-5-tetramethyl-1,3,2-gexabolan-2-Il) pyridine (290 mg, 1.16 mmol), k 3 PO 4 (371 mg, 1.75mmol), and TERT-Butyl N- [(8s, 14s) -21-iodine-18,18-Dimethyl-9,15-Geoxo-4--10,22,28-Tria Penta Cyclo [18.5.2.1^[2,6] .1^[10,14] .0^[23,27]] Nonakosa-1 (26), 2,4,6(29), 20,23 (27), 24-Heptaen-8-Il] Calvimate (500 mg, 0.58 mmol), 1,4-geoxan (5ml) and H 2 PD (DPPF) CL for a mixture with o (1ml) 2 (43 mg, 0.06 mmol) was added.After heating the mixture to 70 ° C and stirring for 2 hours, H 2 O was added and a mixture was extracted with ETOAC (2 × 10 ml).Clean the combined organic layer with brine (10ml) and do anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, Tert-butyl N- [(8s, 14s) -21- [4- (Metoxymethyl) pyridine-3-Il] -18, 18,.18-Dimethyl-9,15-Geoxo-4- [(Trisopyl Syril) Oxy] -16-Oxa-10,22,28-Tria Penta Cyclo [18.5.2.1^[2,6] .1^[10, 14] .0^[23,27]] Nonakosa-1 (26), 2,4,6 (29), 20,23 (27), 24-Heptaen-8-Il] Calvamate (370 mg, 74%The rate) was obtained as a bubble.LCMS: (ESI): M / Z [M+H] C 48 H 67 N 5 O 7 Calculator for Si: 853.6; Active value 854.6.

[0400] Step 3.TERT-Butyl N- [(8s, 14s) -21- [4- (Metoxymethyl) Pyridine-3-Il] -18,18-Dimethyl-9,15-Geoxo-4--16- Oxa-10, 22, 28-Triazapenta Chicho [18.5.2.1^[2,6] .1^[10,14] .0^[23,27]] Nonakosa-1 (26), 2, 4,6 (29), 20,23 (27), 24-Heptaen-8-Il] Calvamate (350mg, 0.41 mmol), CS 2 Co 3 The mixture of (267 mg, 0.82 mmol) and ETI (128 mg, 0.82 mmol) with DMF (4 ml) was stirred overnight at 35 ° C.H 2O was added and a mixture was extracted with ETOAC (2 x 15ml).Wash the combined organic layer with brine (15ml) and do anhydrous NA 2 So 4 It was dried and filtered.The filter solution is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, TERT-butyl N- [(8s, 14s) -22-ethyl-21- [4- (Methoxymethyl) Pyridine-3-Il.] -18,18- Dimethyl-9,15-Geoxo-4- [(Trisopyl Cyril) Oxy] -16- Oxa -10,22,28-Tria Penta Cyclo [18.5.2.1^[2,6]1^[10,14] .0^[23,27]] Nonakosa-1 (26), 2,4,6 (29), 20,23 (27), 24-Heptaen-8-Il] Calvamate (350 mg, 97%yield) was obtained as oil.LCMS (ESI): M / Z [M+H] C 50 H 71 N 5 O 7 Calculator for SI: 881.5; Active value 882.6.

[0401] Step 4.Under the atmosphere of AR, at 0 ° C, tert-butyl N- [(8s, 14s) -22- ethyl-21- [4- (metoxymethyl) pyridine-3-Il] -18,18-dimethyl-9,15-Ciso-4- [(Triisopyl Syril) Oxy] -16-Oxa-10,22,28-Tria Penta Cyclo [18.5.2.1^[2,6] .1^[10,14] .0^[23,27]] Nonakosa-1 (26), 2,4,6 (29), 20,23 (27), 24-Heptaen-8-Il] Carbamate (350 mg, 0.4 mmol), and 1m Tbaf THF(0.48 ml, 0.480 mmol) The mixture with the THF (3 ml) of the solution was stirred for an hour.The mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, TERT-butyln- [(8s, 14s) -22-ethyl-4- hydroxy-21- [4- (Metoxy Methyl) Pyridine-3-Il] -18,18-Dimethyl-9,15-Geoxo-16-Oxa -10,22,28-Tria Penta Cyclo [18.5.2.1^[2,6] .1^[10,14]0^[23,27]] Nonakosa-1 (26), 2,4,6 (29), 20,23 (27), 24-Heptaen-8-Il] Calvamate (230mg, 80%yield)I got it.LCMS (ESI): M / Z [M+H] C 41 H 51 N 5 O 7 Calculator for: 725.4; Active value 726.6.

[0402] Step 5.Under the atmosphere of AR, at 0 ° C, tert-butyl N- [(8s, 14s) -22- ethyl-4- hydroxy-21- [4- (metoxymethyl) pyridine-3-Il] -18,18-dimethyl-9,15-geoxo-16-oxa-10,22,28-triazapenta croco [18.5.2.1^[2,6] .1^[10,14] .0^[23,27]] Nonakosa-1 (26), 2,4,6 (29), 20,23 (27), 24-Heptaen-8-Il] Calvamate (200 mg, 0.28 mmol), a mixture of 1,4-geoxan (2 ml)., 4m HCL in 1,4-geoxan (2 ml, 8 mmol) was added.Warm the mixture to room temperature, stir overnight, concentrate under reduced pressure, (6). 3 S, 4 S ) -4-Amino-1 1 -Etile-2 5 -Hydroxy-1 2 -(4- (metoxymethyl) pyridine-3-Il) -10,10-dimethyl-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-1 (5,3)-Indra-6 (1,3) -Pyridazina-2 (1,3) -Benzenasicrow wandkafan-5,7-Zion (200 mg) was obtained.LCMS (ESI): M / Z [M+H] C 36 H 43 N 5 O 5 Calculator for: 625.3; Active value 626.5.

[0403] Intermediate body 8.TERT-Butyl ((6) 3 S, 4s, Z) -1 1 -Etile-1 2 -(2- ((s) -1-Metoxyethyl) pyridine-3-Il) -10,10-dimethyl-5,7-geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -cirazora-1 (5,3)-Indeal-6 (1,3) --Pyridazina Cyclone De Cafan-4-Il) Calvamate synthesis [Formation]

[0404] Step 1.At room temperature, Methyl (2s) -3- (4-bromo-1,3-Chiasol-2-Il) -2- [(TERT-butoxycalbonil) Amino] Propanote (110g, 301.2mmol), THF (500ml)And H 2 O (200ml) LIOH (21.64g, 903.6 mmol) was added to the solution.After the solution was stirred for 1 hour, it was concentrated under reduced pressure.After adjusting the residue to PH6 with 1m HCL, it was extracted with DCM (3x500ml).NA is the combined organic layer 2 So 4 Dry and filter, concentrate under reduced pressure, (S) -3- (4-bromochiazol-2-Il) -2- ((TERT-butoxycalbonil) amino) Propesite (108g, rough).I got.LCMS (ESI): M / Z [M+H] C 11 H 16 Brn 2 O 4 Calculator for S 351.0; Actual measured value 351.0.

[0405] In the process 2.0 ° C, (S) -3- (4-bromochiazol-2-Il) -2- (((TERT-butoxycalbonyl) amino) amino) in the DCM (500ml) solution of propepolic acid (70g, 199.3 mmol)., Methyl (3s) -1,2-diazinan-3-carboxylethrissus (trifluoro acetic acid) salt (111.28g, 298.96 mmol), NMM (219.12 ml, 1993.0mmol), EDCI (76.41g, 398.6 mmol), andHOBT (5.39g, 39.89mmol) was added.The solution was heated to room temperature and stirred for 1 hour.Next, the reaction material H 2 I quenched with o (500ml) and extracted with ETOAC (3 x 500ml).NA is the combined organic layer 2 So 4 It was dried and filtered, and concentrated under reduced pressure.The residue is purified by silica gel column chromatography, methyl (S) -1- (S) -3- (4-bromochiazol-2-Il) -2- ((TERT-butoxycalbonil) amino) HexaHydropyridadin-3-Carboxilate was obtained (88.1g, 93%yield).LCMS (ESI): M / Z [M+H] C 17 H 26 Brn 4 O 5 Calculator for S: 477.1; Active value 477.1.

[0406] Step 3.At room temperature, 3- (5-bromo-1-ethyl-2- (2- (S) -1-metoxyethyl) pyridine-3-Il) -1H-Indole-3-Il) -2,2- 2,2-DimethylPropane-1-all (60g, 134.7 mmol) toluene (500ml) solution, bis (Pinakorat) dibolon (51.31g, 202.1 mmol), PD (DPPF) CL 2 (9.86g, 13.4 mmol) and KOAC (26.44g, 269 mmol) were added.The reaction mixture was heated to 90 ° C. and stirred for 2 hours.Next, the reaction solution was cooled to room temperature and concentrated under reduced pressure.The residue is purified by silica gel column chromatography, (s) -3- (1-ethyl-2- (2- (1-metoxyethyl) pyridine -3-Il) -5- (4,4,5,5,5)-Tetramethyl-1,3,2-Gexabolan-2-Il) -1H-Indole-3-Il) -2,2, 2, 2, 2,2-Dimethylopan-1-All obtained (60.6g, 94%yield).LCMS (ESI): M / Z [M+H] C 29 H 42 Bn 2 O 4 Calculator for: 493.32; Active value 493.3.

[0407] Step 4.At room temperature, (s) -3- (1-ethyl-2- (2- (1-metoxyethyl) pyridine-3-Il) -5- (4,4,5,5-Tetramethyl-1,3, 3,2-Gexabolan-2-Il) -1H-Indole-3-Il) -2,2-Dimethyl propane-1-all (30g, 60.9mmol) toluene (600 ml), geoxan (200 ml), and h 2 O (200ml) Methyl (S) -1- (S) -3- (4-bromochiazole -2-Il) -2- ((TERT-butoxycalbonil) Amino) Propoyol-Calvoxilate (43.62g, 91.4mmol), K 3 PO 4 (32.23g, 152.3mmol), and PD (DPPF) CL 2 (8.91g, 12.18mmol) was added.The obtained solution was heated to 70 ° C and stirred overnight.Next, cool the reaction mixture to room temperature and H. 2I quenched with o (200ml).The mixture is extracted with ETOAC and the combined organic layer is NA 2 So 4 It was dried and filtered, and concentrated under reduced pressure.The residue is purified by silica gel column chromatography, methyl (S) -1- ((s) -2- ((TERT-butoxycalbonyl)) amino) -3- (4- (1-ethyl-3- (3- (3-3-))Hydroxy-2,2-dimethyl propyl) -2- (2- (s) -1-metoxyethyl) pyridine-3-Il) -1H-Indole-5-Il) Chiazole-2-Il) Proponoy) HexahydroPilidadine-3-Carboxilate was obtained (39.7g, 85%yield).LCMS (ESI): M / Z [M+H] C 40 H 55 N 6 O 7 Calculator for S: 763.4; Active value 763.3.

[0408] Step 5.At room temperature, methyl (s) -1- ((s) -2- (TERT-butoxycalbonil) amino) -3- (4- (1-ethyl-3- (3-hydroxy-2,2-dimethyl propille)) -2- (2- (S) -1-Methoxyethyl) Pyridine-3-Il) -1H-Indole-5-Il) Chirazol-2-Il) Proponoy) Hexhadropilidadine-3-Carboxilate (39.7G, 52.0 mmol) THF (400ml) and H 2 O (100ml) LIOH · h to solution 2 O (3.74g, 156.2mmol) was added.After the mixture was stirred for 1.5 hours, it was concentrated under reduced pressure.After the residue was acidified to pH6 with 1m HCL, it was extracted with DCM (3 × 1000ml).NA is the combined organic layer 2 So 4 Dry and filter, concentrate under reduced pressure, (s) -1-((s) -2- (TERT-butoxycalbonyl) amino) -3- (4- (1-ethyl-3-)(3-hydroxy-2,2-dimethyl propyl) -2- (2- ((s) -1-metoxyethyl) pyridine-3-Il) -1H-Indole-5-Il) Chirazol-2-Il) Proponoy) Hexahydropyridazine-3-Carboxylic acid (37.9g, rough).LCMS (ESI): M / Z [M+H] C 39 H 53 N 6 O 7 Calculator for S: 749.4; Active value 749.4.

[0409] Step 6.0 ° C, (s) -1-((s) -2- (TERT-butoxycalbonyl) amino) -3- (4- (1-ethyl-3- (3-hydroxy-2,2,2)-2- (2- (S) -1-Metoxyethyl) Pyridine-3-Il) -1H-Indole-5-Il) Chirazol-2-Il) Proponoy) Hexahydropyridadine-3-CarbonEDCI (271.63g, 1416.9 mmol) was added to the solution of acid (37.9g, 50.6 mmol), Hobt (34.19g, 253.0 mmol), and DIPEA (264.4 ml, 1518 mmol) DCM (4L) solution.The obtained mixture was heated to room temperature and stirred overnight.Next, the reaction mixture H 2 I quenched with O and was washed with 1m HCL (4x1L).The organic layer was separated and concentrated under reduced pressure.The residue is purified by silica gel column chromatography by TERT-Butyl ((6) 3 S, 4s, Z) -1 1 -Etile-1 2 -(2- ((s) -1-Metoxyethyl) pyridine-3-Il) -10,10-dimethyl-5,7-geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -Cisora 1 (5,3)-Indra-6 (1,3) -Pyridazina Cyclone De Cafan-4-Il) I got a carbamate (30g,81%yield).LCMS (ESI): M / Z [M+H] C 39 H 51 N 6 O 6 Calculator for S: 731.4; Active value 731.3.

[0410] TERT-Butyl ((6) (6) at the process 7.0 ° C 3 S, 4s, Z) -1 1 -Etile-1 2 -(2- ((s) -1-Metoxyethyl) pyridine-3-Il) -10,10-dimethyl-5,7-geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -cirazora-1 (5,3)-Indra-6 (1,3) -Pyridazina Cyclone De Cafan-4-Il) Calvamate (6g, 8.21mmol)TFA (30ml) was added to the DCM (60ml) solution.After stirring the mixture for 1 hour, concentrate under reduced pressure, (6) 3 S, 4s, Z) -4-Amino-1 1 -Etile-1 2 -(2- ((s) -1-Metoxyethyl) pyridine-3-Il) -10,10-dimethyl-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -cirazora-1 (5,3)-Indeal-6 (1,3) -Pyridazina Cyclone De Cafan-5,7-I got (7.0g, Rough).LCMS (ESI): M / Z [M+H] C 34 H 42 N 6 O 4 Calculation value for S 631.3; Actual measured value: 630.3.

[0411] Intermediate body 9.(S) -3-bromo-5-iodine-2- (1-metoxyethyl) pyridine synthesis.

[0412] [Formation]

[0413] Step 1.3-Bromo-2- [(1s) -1-Methoxyethyl] Pyridine (80.00g, 370.24mmol, 1.00 equivalent) and biscuits (Pinakorat) dibolon (141.03g, 555.3 mmol, 1.50 equivalents), THF (THF).DTBBY (14.91g, 55.5 mmol) and chloro (1,5-cyclooctagiene) Iridium (I) Iridium (I), two-quantity (I), were added to the 320ml) solution to 320ml.The obtained mixture was stirred at 75 ° C for 16 hours in an argon atmosphere.The mixture was concentrated under reduced pressure.Dissolve the obtained mixture in ETOAC (200ml) to the mixture. 2 Co 3 Adjusted to pH10 by (40g) and NAOH (10g) (4: 1) aqueous solution (600 ml).The water layer was extracted with ETOAC (800ml).The aqueous phase is acidified by HCL (6n) to pH = 6, the desired solid is settled, 5-bromo-6- [(1s) -1-metoxyethyl] pyridine-3-Irborolonic acid (50g, 52.0A percentage of percentage) was obtained as a pale yellow solid.LCMS (ESI): M / Z [M+H] C 8 H 11 Bbrno 3 Calculated to 259.0; Active value 260.0.

[0414] Step 2.5-Bromo-6- [(1s) -1-Methoxyethyl] Pyridine-3-Irbore-lonic acid (23.00g, 88.5 mmol), NIS (49.78g, 221.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.2.28g, 221.2, 221.2, 88.5 ml, 22MMOL) was added at room temperature in an argon atmosphere.The obtained mixture was stirred in an argon atmosphere overnight.The obtained mixture was concentrated under reduced pressure.The obtained mixture is dissolved in DCM (2.1L) and NA 2 S 2 O 3 Washed with (3x500ml).Oils of organic layers na 2 So 4 I dried it.After filtration, the film was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, and (S) -3-bromo-5-iodine-2- (1-metoxyethyl) pyridine (20g, 66.0%yield) was obtained.LCMS (ESI): M / Z [M+H] C 8 H 9 Calculation value for BRINO 340.9; Actual measured value 341.7.

[0415] Intermediate body 10.TERT-Butyl ((6) 3 S, 4s, Z) -11-Ethyl-1 2 -(2- (S) -1-Metoxyethyl) -5- (4-methylpipipelladin-1-Il) Pyridine-3-Il) -10,10-Dimethyl-5,7-Geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -cirazora-1 (5,3)-Indeal-6 (1,3) --Pyridazina Cyclone De Cafan-4-Il) Calvamate synthesis [Formation]

[0416] Step 1.3L Mitsuku Maru Flask, which maintains the inactive atmosphere of the argon, 3-bromo-5-iode-2- [(1S) -1-Metoxyethyl] pyridine (147g, 429.8 mmol),Benzyl Piperazine-1-Carboxylate (94.69g, 429.8mmol), PD (OAC) 2 (4.83g, 21.4mmol), BINAP (5.35g, 8.6mmol), CS 2 Co 3 (350.14g, 1074.6mmol) and toluene (1L) were added.The obtained solution was stirred at 100 ° C during the oil bath overnight.After the reaction, the reaction mixture was cooled to 25 ° C.The obtained mixture was concentrated under reduced pressure.The residue was filled with silica gel column using ethyl acetate / hexane (1: 1).By removing the solvent under reduced pressure, benzyl (S) -4- (5-bromo-6- (1-metoxyethyl) pyridine-3-Il) Piperadin-1-Carboxylate (135g, 65.1%yield) Won as a dark yellow solid.LCMS (ESI): M / Z [M+H] C 20 H 24 Brn 3 O 3 Calculated 433.1; Active value 434.1.

[0417] Step 2.Purging the inactive atmosphere of the argon and maintaining it, 3L Mitsuku Maru Ripples, Benzyl 4- [5-Bromo-6- [(1S) -1S) -1-Metoxyethyl] Pyridine-3-Il Pipelladin-1-Carboxylate (135g, 310.8 mmol), bis (Pinakorat) dibollon (86.82g, 341.9mmol), PD (DPPF) CL 2 (22.74g, 31.0 mmol), KOAC (76.26g, 777.5mmol), and toluene (1L).The obtained solution was stirred at 90 ° C during the oil bath for two days.The reaction mixture was cooled to 25 ° C.The obtained mixture was concentrated.The residue was filled with a neutral aluminum caram using ethyl acetate / hexane (1: 3).Removed a solvent under reduced pressure, benzyl (S) -4- (6- (1-metoxyethyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxabolan-2-)Il) Pyridine-3-Il) Pipelladin-1-Carboxilate (167g, rough) was obtained as a dark yellow solid.LCMS (ESI) M / Z: [M+H] C 26 H 36 Bn 3 O 5 Calculator for: 481.3; Active value 482.1.

[0418] Step 3.(S) -4- (6- (1-metoxyethyl) -5- (4,4,5,5-5-Tetra) in the 3L Mitsukuchi Marushu Flask, which maintains the inert atmosphere of the argonMethyl-1,3,2-Gexabolan-2-Il) Pyridine-3-Il) Piperadin-1-Carboxylate (167g, 346.9mmol), 5-Bromo-3- [3-Oxy] -2,2-dimethyl propyl] -2-iodine-1H-Indole (224.27g, 346.9mmol), PD (DPPF) CL 2 (25.38g, 34.6 mmol), geoxan (600ml), H 2 O (200ml), k 3 PO 4 (184.09g, 867.2mmol) and toluene (200ml) were added.The obtained solution was stirred at 70 ° C during the oil bath overnight.After the reaction, the reaction mixture was cooled to 25 ° C.The obtained mixture was concentrated.The residue was filled with silica gel column using ethyl acetate / hexane (1: 1).By removing the solvent under reduced pressure, benzyl (S) -4- (5- (5-bromo-3- ((TERT-butyl jet phenylsyril) oxy) -2,2,2-dimethyl propyl)-1H-Indole-2-Il) -6- (1-Metoxyethyl) Pyridine-3-Il) Piperadin-1-Carboxylate (146g, 48.1%yield) was obtained as a yellow solid.LCMS (ESI): M / Z [M+H] C 49 H 57 Brn 4 O 4 Calculation value for SI 872.3; Active value 873.3.

[0419] Step 4.N 2 In the atmosphere, at 0 ° C, Benzyl (S) -4- (5-bromo-3- (3- ((TERT-butt-butyuljphenylsyil) oxy) -2,2-dimethyl propyl) -1H-Indole-2-Il) -6- (1-metoxyethyl) pyridine-3-Il) Piperadin-1-Calvoxilate (146g, 167.0mmol) and CS 2 Co 3 In (163.28g, 501.1mmol), a stirring mixture with DMF (1200ml), c 2 H 5 I (52.11g, 334.0mmol) was added in small parts.The final reaction mixture was stirred at 25 ° C for 12 hours.The desired product could be detected by LCMS.The obtained mixture was diluted with EA (1L) and was washed with brine (3 × 1.5L).Oils of organic layers na 2 So 4 I dried it.After filtration, concentrate the film under reduced pressure to benzyl (S) -4- (5- (5-bromo-3- ((TERT-butt-butyuljphenylsyril) oxy) -2,2,2-dimethyl propille).-1- ethyl-1H-Indole-2-Il) -6- (1-Metoxyethyl) Pyridine-3-Il) Pipelladin-1-Carboxylate (143g, rough) is gained as a yellow solid, and further refinement.It was used directly in the next process.LCMS (ESI): M / Z [M+H] C 51 H 61 Brn 4 O 4 Calculator for SI: 900.4; Active value 901.4.

[0420] Step 5.Benzyl Benzyl (S) -4- (5- (5-Bromo-3- (3- ((TERT-Butyl Jefenylsyril) Oxy) -2,2-Dimethyl Propil) -1-ethyl-1H-Indole -2-Il) -6- (1-metoxyethyl) pyridine-3-Il) Pipelladin-1-Carboxylate (143g, 158.5 mmol), DMF (1250 ml) stirring mixture adds CSF (72.24g, 475.5mmol).did.Next, the reaction mixture 2 The mixture was stirred at 60 ° C for two days under the atmosphere.The desired product could be detected by LCMS.The obtained mixture was diluted with EA (1L) and was washed with brine (3x1L).Next, the organic phase was concentrated under reduced pressure.The residue is purified by silica gel column chromatography (dissolved in PE / EA (1 / 3)) to benzyl (S) -4- (5- (5-bromo-1-ethyl-3- (3-hydroxy-2) -2., 2-dimethyl propyl) -1H-Indole-2-Il) -6- (1-metoxyethyl) pyridine-3-Il) Piperadin-1-Carboxylate A (38g, 36%yield, 3 minutes LCMS (0.1)In%fa), RT = 1.677 minutes), and B (34g, 34%yield, 3 minutes LCMS (0.1%FA), RT = 1.578 minutes), both atlop straps, both as yellow solids.Obtained.LCMS (ESI): M / Z [M+H] C 35 H 43 Brn 4 O 4 Calculator for: 663.2; Active value 662.2.

[0421] Step 6.2-dimethyl propyl) -1H-Indole-2-Il) -6- (1-metoxyethyl) pyridine-3-Il) Piperadin-1-Carboxylate A (14g, 21.1mmol), Bis (Pinakorato) Gibollon (5.89)G, 23.21mmol), PD (DPPF) CL 2 (1.54g, 2.1 mmol), KOAC (5.18g, 52.7mmol), and toluene (150ml) were placed.The obtained solution was stirred at 90 ° C during the oil bath for 5 hours.The reaction mixture was cooled to 25 ° C.The obtained mixture was concentrated.The residue is purified by silica gel column chromatography (dissolved in PE / EA (1 / 3)) to benzyl (S) -4- (5- (1-ethyl-3- (3-hydroxy-2,2-dimethyl (3-hydroxy) -2,2-dimethyl).Propil) -5- (4,4,5,5-Tetramethyl-1,3,2-Gexabolan-2-Il) -1H-Indole-2-Il) -6- (1-Metoxyethyl) Pyridine-3-Il) Piperadin-1-Carboxylate (12g, 76.0%yield) was obtained as a yellow solid.LCMS (ESI): M / Z [M+H] C 41 H 55 Bn 4 O 6 Calculated 710.4; Active value 711.3.

[0422] Step 7.Benzyl (S) -4- (1-ethyl-3- (3-Hydroxy-2, 2, Dimethyl Propill) -5 in the 250ml round bottom flask, which is maintained by purging and maintaining the inactive atmosphere of argon.-(4,4,5,5-5- Tetramethyl-1,3,2-Gexabolan-2-Il) -1H-Indole-2-Il) -6- (1-Metoxyethyl) Pyridine-3-Il) Pipelladin-1-Carboxylate (10.8g, 15.2mmol), methyl (3s) -1- [(2s) -3- (4-bromo-1,3-chia zol-2-Il) -2- [(TERT-butoxy)Carbonil) Amino] Proponoyl] -1,2-Giazinan -3-Carboxylate (7.98g, 16.7 mmol), PD (DTBPF) CL 2 (0.99g, 1.52mmol), K 3 PO 4 (8.06g, 37.9mmol), toluene (60ml), dioxan (20ml), H 2O (20ml) was placed.The obtained solution was stirred at 70 ° C during the oil bath for 3 hours.The reaction mixture was cooled to 25 ° C.The obtained solution was extracted with ETOAC (2 × 50 ml) and concentrated under reduced pressure.The residue was filled with silica gel column using ethyl acetate / hexane (10: 1).By removing the solvent, methyl (s) -1- ((s) -3- (4- ((Benzyl oxy) carbonyl) carbonyl) piperadin-1-ol) -2-(S) -1-metoxyethyl) pyridine-3-Il) -1-ethyl-3- (3-hydroxy-2,2-dimethyl propyl) -1H-Indole-5-Il) --2-Il)-2- ((TERT-butoxycarbonil) Amino) Proponoyl) Hexahydropyridazine-3-Carboxylate (8g, 50.9%yield) was obtained as a yellow solid.LCMS (ESI): M / Z [M+H] C 52 H 68 N 8 O 9 Calculation value for S 980.5; Active value 980.9.

[0423] Step 8.Methyl (s) -1- ((s) -3- (4- (4- ((Benzyloxy) carbonyl) carbonyl) Piperadin-1-Il) -2- ((s) -1-metoxy)Ethyl) Pyridine-3-Il) -1-ethyl-3- (3-hydroxy-2,2-dimethyl propyl) -1H-Indole-5-Il) Chirazole-2-Il) -2- (TERT-ButoxyCarbonil) Amino) Proponoyl) Hexhadropyridadin-3-carboxylate (12g, 12.23 mmol), THF (100ml) / h 2 In the stirring mixture of o (100 ml), n 2 LIOH (2.45g, 61.1 mmol) was added in the atmosphere, and the obtained mixture was stirred at 25 ° C. 25 ° C.The desired product could be detected by LCMS.THF was concentrated under reduced pressure.At 0 ° C, HCL (1N) caused the pH of the aqueous phase to 5 to 5.The water layer was extracted with DCM (3x100ml).Concentrate the organic phase under reduced pressure, (s) -1- ((s) -3- (4- ((Benzyl oxy) carbonyl) carbonyl) piperadin-1-Il)-2- ((s) -1-Metoxyethyl) Pyridine-3-Il) -1-ethyl-3- (3-hydroxy-2,2-dimethyl propyl) -1H-Indole-5-Il) Chiazol-2-Il) -2- ((TERT-butoxichalbonil) Aminool) Proponoyl) Hexhadropyridadin-3-carboxylic acid (10g, 84.5%yield) was obtained as a pale yellow solid.LCMS (ESI): M / Z [M+H] C 51 H 66 N 8 O 9 Calculation value for S 966.5; Active value 967.0.

[0424] Step 9.(S) -1- ((S) -3- ((4) (((()) (Benzlox) (((Ben) Benzyulox, (((Ben), Benzlox,) (Benzlox,) (Benzylox, (Benzylox,) (Benzylox, ((Ben), Benzylox,) (Benzylox, ((Ben), Benzylox, ((Ben), Benzylox, ((Ben), Benzyl ", ((Ben), Benzyl,) ((Ben), Benzyloxy)) is) Calbonyl) Piperazine-1-Il) -2-((s) -1- Methoxyethyl) Pyridine-3-Il) -1- ethyl-3- (3-hydroxy-2,2-dimethyl propille) -1H-Indole-5-Il) Chiazole-2-Il) -2- ((TERT-Butoxycarbonil) Amino) Proponoyl) Hexhadropyridadin-3-Carboxylic acid (18g, 18.61 mmol), ACN (1.8L), DIEA (96.21)G, 744.4mmol), EDCI (107.03g, 558.3mmol), and Hobt (25.15g, 186.1mmol) were placed.The obtained solution was stirred at 25 ° C. overnight.After the reaction was completed, the obtained mixture was concentrated under reduced pressure.The obtained solution was diluted with DCM (1L).The obtained mixture was washed with HCL (3x1L, 1N aqueous solution).The obtained mixture was washed with water (3x1L).Next, the organic layer was concentrated, and the residue was filled with ethyl acetate / hexane (1: 1) in silica gel column.By removing the solvent under reduced pressure, benzyl 4- (5- (6 (6) 3 S, 4s, Z) -4- ((TERT-butoxycarbonil) Amino) -1 1 -10,10-dimethyl-5,7-geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -cirazola-1 (5,3)-Indela-6 (1,3) --Pyridazina Cyclone De Cafan-1 2 -Il) -6- (s) -1-Metoxyethyl) Pyridine-3-Il) Piperadin-1-Carboxylate (10.4g, 54.8%yield) was obtained as a pale yellow solid.LCMS (ESI): M / Z [M+H] C 51 H 64 N 8 O 8 Calculation value for S 948.5; Active value 949.3.

[0425] Step 10.Benzyl 4- ((6- (6) (6) (6- (6) (6 (6), (6 (6), in the 250ml round bottom flask, maintained by purging nitrogen reduction. 3 S, 4s, Z) -4- ((TERT-butoxycarbonil) Amino) -1 1 -10,10-dimethyl-5,7-geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -cirazola-1 (5,3)-Indela-6 (1,3) --Pyridazina Cyclone De Cafan-1 2 -Il) -6-(S) -1-Metoxyethyl) Pyridine-3-Il) Piperadin-1-Carboxilate (10.40g, 10.9mmol), PD (OH) 2 / C (5g, 46.9mmol), MEOH (100ml) were placed.The obtained solution is 2 atm 2 In the atmosphere, it was stirred at 25 ° C for 3 hours.The solid was filtered and the filter mass was washed with meoh (3x100ml).Next, the combined organic phase is concentrated under reduced pressure, and TERT-Butyl ((6) 3 S, 4s, Z) -11-Ethyl-1 2 -(2- ((s) -1-metoxyethyl) -5- (piperadin-1-Il) pyridine-3-Il) -10,10-dimethyl-5,7-geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -cirazora-1 (5,3)-Indra-6 (1,3) -Pyridazina Cyclone De Cafan-4-Il) Calvamate (8.5g, 90.4%The yield) was obtained as a pale yellow solid.LCMS (ESI): M / Z [M+H] C 43 H 58 N 8 O 6 Calculation value for S 814.4; Active value 815.3.

[0426] Step 11.In the 1000ml round bottom flask, which maintains the nitrogen reduction atmosphere, TERT-Butyl ((6) 3 S, 4s, Z) -11-Ethyl-1 2 -(2- ((s) -1-metoxyethyl) -5- (piperadin-1-Il) pyridine-3-Il) -10,10-dimethyl-5,7-geoxo-6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 -Hexahydro-1 1 H-8-Oxa-2 (4,2) -Cisora 1 (5,3)-Indra-6 (1,3) -Pyridazina Cyclone De Cafan-4-Il) Calvamate (8.5g, 10.4mmol), MEOH (100ml), ACOH (1.88g, 31.2 mmol), and stirred for 15 minutes...

Claims

1. The structure of formula Ig: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R ９ )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-, L has the structure of formula IIa: 【Chemistry 2】 [In the formula, X a is absent or N; R 14 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 3 cycloalkyl; and L 2 is absent, —C(O)—, —SO 2 —, optionally substituted C 1 -C 4 alkylene, or optionally substituted C 1 -C 4 heteroalkylene; At least one of X a , R 14 , or L 2 is present; or L has the structure of formula IIb: 【Chemistry 3】 [In the formula, o is 0 or 1, X b is C(O) or SO 2 ; R 15 is hydrogen or optionally substituted C 1 -C 6 alkyl; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; and L 3 is absent, -C(O)-, -SO 2 -, optionally substituted C 1 -C 4 alkylene, or optionally substituted C 1 -C 4 heteroalkylene; W is hydrogen, optionally substituted amino, optionally substituted C １ -C ４ Alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ Aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ guanidinoalkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R ２ is C １ -C ６ alkyl or 3- to 6-membered cycloalkyl; R ７ is C １ -C ３ is alkyl, R ８ is C １ -C ３ is alkyl, R ９ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; X ｅ is N, CH, or CR １７ and X ｆ is N or CH; R １２ is an optionally substituted C １ -C ６ Alkyl, or optionally substituted C １ -C ６ Heteroalkyl, and R １７ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; The compound, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered arylene.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is an optionally substituted 5- to 6-membered heteroarylene.

4. R ９ is optionally substituted C １ -C ６ 4. The compound of any one of claims 1 to 3, which is alkyl, or an optionally substituted 3-6 membered cycloalkyl, or a pharma- ceutically acceptable salt thereof.

5. 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein W is hydrogen.

6. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein W is optionally substituted amino.

7. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein W is an optionally substituted amide.

8. W is an optionally substituted C １ -C ４ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

9. W is an optionally substituted C １ -C ４ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

10. W is an optionally substituted C １ -C ４ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, which is hydroxyalkyl.

11. W is an optionally substituted C １ -C ４ The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, which is aminoalkyl.

12. W is an optionally substituted C １ -C ４ The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

13. W is an optionally substituted C １ -C ４ The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, which is guanidinoalkyl.

14. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 11-membered heterocycloalkyl.

15. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein W is an optionally substituted 3-8 membered cycloalkyl.

16. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein W is an optionally substituted 3-8 membered heteroaryl.

17. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein W is an optionally substituted 6-10 membered aryl.

18. The following: 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 【Chemistry 4-5】 【Chemistry 4-6】 【Chemistry 4-7】 【Chemistry 4-8】 【Chemistry 4-9】 【Chemistry 4-10】 【Chemistry 4-11】 【Chemistry 4-12】 【Chemistry 4-13】 【Chemistry 4-14】 【Chemistry 4-15】 【Chemistry 4-16】 【Chemistry 4-17】 【Chemistry 4-18】 【Chemistry 4-19】 【Chemistry 4-20】 【Chemistry 4-21】 【Chemistry 4-22】 【Chemistry 4-23】 【Chemistry 4-24】 【Chemistry 4-25】 【Chemistry 4-26】 【Chemistry 4-27】 【Chemistry 4-28】 【Chemistry 4-29】 【Chemistry 4-30】 【Chemistry 4-31】 【Chemistry 4-32】 【Chemistry 4-33】 【Chemistry 4-34】 【Chemistry 4-35】 【Chemistry 4-36】 【Chemistry 4-37】 【Chemistry 4-38】 【Chemistry 4-39】 【Chemistry 4-40】 【Chemistry 4-41】 【Chemistry 4-42】 【Chemistry 4-43】 【Chemistry 4-44】 【Chemistry 4-45】 【Chemistry 4-46】 【Chemistry 4-47】 【Chemistry 4-48】 【Chemistry 4-49】 【Chemistry 4-50】 【Chemistry 4-51】 【Chemistry 4-52】 【Chemistry 4-53】 【Chemistry 4-54】 【Chemistry 4-55】 【Chemistry 4-56】 【Chemistry 4-57】 【Chemistry 4-58】 【Chemistry 4-59】 【Chemistry 4-60】 【Chemistry 4-61】 【Chemistry 4-62】 【Chemistry 4-63】 【Chemistry 4-64】 【Chemistry 4-65】 【Chemistry 4-66】 【Chemistry 4-67】 【Chemistry 4-68】 【Chemistry 4-69】 【Chemistry 4-70】 【Chemistry 4-71】 【Chemistry 4-72】 【Chemistry 4-73】 【Chemistry 4-74】 【Chemistry 4-75】 【Chemistry 4-76】 【Chemistry 4-77】 【Chemistry 4-78】 【Chemistry 4-79】 【Chemistry 4-80】 【Chemistry 4-81】 【Chemistry 4-82】 【Chemistry 4-83】 【Chemistry 4-84】 【Chemistry 4-85】 【Chemistry 4-86】 【Chemistry 4-87】 【Chemistry 4-88】 【Chemistry 4-89】 【Chemistry 4-90】 【Chemistry 4-91】 【Chemistry 4-92】 【Chemistry 4-93】 【Chemistry 4-94】 【Chemistry 4-95】 【Chemistry 4-96】 【Chemistry 4-97】 1. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

20. 20. The pharmaceutical composition of claim 19 for use in the treatment of cancer.

21. 21. The pharmaceutical composition of claim 20, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer.

22. 22. The pharmaceutical composition of claim 21, wherein the cancer comprises a Ras mutation.

23. 23. The pharmaceutical composition of claim 22, wherein the Ras mutation is at position 12, 13, or 61.

24. 23. The pharmaceutical composition of claim 22, wherein the Ras mutation is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, or K-Ras Q61L.

25. The pharmaceutical composition of claim 19 for use in treating a Ras protein-associated disease.

26. The pharmaceutical composition according to any one of claims 20 to 25, wherein the pharmaceutical composition is used in combination with an additional anti-cancer therapy.

27. 27. The pharmaceutical composition of claim 26, wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

28. 28. The pharmaceutical composition of claim 26 or 27, wherein the additional anti-cancer therapy is an SHP2 inhibitor.

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