TW201307315A - New triazolylphenyl sulfonamides as serine/threonine kinase inhibitors - Google Patents

Abstract

The present invention encompasses compounds of general formula (I) wherein the groups R2 to R4, A, X and m are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, pharmaceutical preparations which contain compounds of this kind and their use as medicaments.

Description

Novel triazolyl phenylsulfonamide as a serine/threonine kinase inhibitor

The present invention relates to the novel triazolyl phenylsulfonamide of the general formula (I) Wherein the radicals R ² to R ⁴ , A , X and m have the meanings given in the scope of the patent application and the specification; pharmaceutical preparations containing such compounds and their use as medicaments.

Various fluorine-substituted phenylsulfonamides as modulators of various kinases are described in WO 2009/012283.

It is an object of the present invention to indicate novel triazolyl phenylsulfonamides useful for the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation. The triazolyl phenylsulfonamide of the present invention is characterized by its great inhibitory effect on B-Raf V600E and its improved high anti-tumor cell (e.g. melanoma cell) potency, which is selected by B-Raf V600E Sexual inhibition is achieved and can also be shown in vivo. In addition to inhibition and cellular potency, these compounds additionally have good pharmacokinetic properties. Due to this overall overview, the compounds of the invention are suitable for drug development.

The RAS-RAF-MAPK (mitogen-activated protein kinase) signaling pathway plays a key role in the transmission of proliferative signals produced by cell surface receptors and cytoplasmic signaling elements into the nucleus. The constitutive activation of this pathway is associated with a malignant transformation of several oncogenes. Activating mutations in RAS occur in approximately 15% of cancers, and recent data show that B-RAF mutations occur in approximately 7% of cancers (Wellbrock et al, Nature Rev. Mol. Cell Biol. 2004, 5: 875-885), thereby It is identified as another important oncogene in this pathway. In mammals, the RAF family of serine/threonine kinases contains three members: A-RAF, B-RAF, and C-RAF. However, activating mutations have only been identified in B-RAF to date, highlighting the importance of this isoform. B-RAF is the major isoform that couples RAS to MEK, and C-RAF and A-RAF signaling to ERK only fine-tunes cellular responses (Wellbrock et al, Nature Rev. Mol. Cell Biol. 2004, 5 :875-885). The most common cancer mutation in B-RAF causes the exchange of proline and glutamic acid (V600E) at position 600 of the protein, which may significantly enhance B-RAF activity due to its negative charge mimicking activated ring phosphorylation. (Wan et al., Cell 2004, 116: 855-867). The highest incidence of B-RAF V600 mutations occurred in malignant melanoma (38%), thyroid cancer (38%), colorectal cancer (10%), biliary tract cancer (12%), and ovarian cancer (12%). However, it also appears in a variety of other cancers at low frequency (mutation frequency is based on COSMIC ( Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute ) 49th edition, September 29, 2010). The literature supports the hypothesis that B-RAF ^V600E mutant tumor cells appear to rely primarily on sustained activation of this pathway (a phenomenon known as "oncogene addiction"), while normal B-RAF ^wt cells use a wider range of signals. This situation provides a therapeutically impaired Achilles' heel that can be treated with a B-RAF ^V600E with a somatic mutation using an orally administered B-RAF inhibitor.

The pivotal role of B-RAF ^V600E in abnormal ERK signaling and resulting tumor formation has been demonstrated in several independent experimental methods such as: in vitro and in vivo overexpression of oncogenic/mutant B-RAF (Wan et al. , Cell 2004, 116: 855-867; Wellbrock et al, Cancer Res. 2004, 64: 2338-2342), in vitro siRNA blocking gene expression (Karasarides et al, Oncogene 2004, 23: 6292-6298) or inducibility A short hairpin RNA xenograft model in which functionally acquired B-RAF signaling is found to be strongly associated with tumorigenicity in vivo (Hoeflich et al, Cancer Res. 2006, 66:999-1006).

Treatment with B-RAF ^V600E mutant melanoma or colon cancer cells induces a B-RAF inhibition phenotype (eg, decreased MEK and phospho-ERK levels, decreased cyclin D performance, and induced p27 expression). Therefore, these cells are locked in the G1 phase of the cell cycle and do not proliferate.

It has now surprisingly been found that compounds of the formula (I) in which the radicals R ² to R ⁴ , A , X and m have the meanings given below serve as specific signals associated with the control of cell proliferation An inhibitor of the enzyme. Thus, the compounds of the invention may, for example, be used to treat diseases associated with the activity of such signaling enzymes and characterized by excessive or abnormal cell proliferation.

The invention therefore relates to compounds of the general formula (I) Wherein (A0)R ² is a group optionally substituted by one or more of the same or different R ^b1 and/or R ^c1 selected from C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _6-10 aryl, 5 to 10 membered heteroaryl, and 3 to 10 a heterocyclic group, or R ² is -NR ^c1 R ^c1 ; each R ^{b1 is} independently selected from -OR ^c1 , -NR ^c1 R ^c1 , halogen, -CN, -C(O)R ^c1 , -C(O) OR ^c1 , -C(O)NR ^c1 R ^c1 , -S(O) ₂ R ^c1 , -S(O) ₂ NR ^c1 R ^c1 , -NHC(O)R ^c1 and -N(C _1-4 alkyl C(O)R ^c1 , and a divalent substituent=O, wherein the divalent substituent=O can only be a substituent in a non-aromatic ring system; each R ^c1 independently of one another represents hydrogen or a group selected from Group: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _{6- 10} aryl, 5 to 10 membered heteroaryl and 3 to 10 membered heterocyclic; - (B0) R ³ is selected from the group consisting of hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, -CN, -NH(C _1-4 alkyl) and -N(C _1-4 alkyl) ₂ ;-- ( C0) Ring A is 5 to 10 membered heteroaryl; -- (D0)m represents the number 0, 1 or 2; each R ⁴ independently of each other representing a group substituted with one or more identical or different R ^a2 and/or R ^{b2 ,} optionally selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _6-10 aryl, 5 to 10 membered heteroaryl and 3 to 11 membered heterocyclic, Or independently selected from -OR ^a3 , -NR ^a3 R ^a3 , -N(OR ^a3 )R ^a3 , halogen, -CN, -C(O)R ^a3 , -C(O)OR ^a3 , -C(O) NR ^a3 R ^a3 , -C(NH)NR ^a3 R ^a3 , -S(O) ₂ R ^a3 , -S(O) ₂ NR ^a3 R ^a3 , -NHC(O)R ^a3 and -N(C _1-4 Alkyl)C(O)R ^a3 ; each R ^a2 independently of one another represents a group optionally substituted by one or more of the same or different R ^{b 2} and/or R ^{c 2} , which is selected from C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^b2 Independently selected from -OR ^c2 , -NR ^c2 R ^c2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC(O) R ^c2 and -NHC(O)OR ^c2 ; each R ^c2 independently of one another represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, C _4-6 cycloalkenyl, and 3-10 heterocycle Wherein the heterocyclic groups optionally substituted with one or more identical or different substituents selected from the group: halogen, C _1-6 alkyl and -C (O) -C _1-6 alkyl; each R ^a3 Independently from each other, represents hydrogen or, optionally, a group substituted by one or more of the same or different R ^{b 3} and/or R ^c3 selected from C _1-6 alkyl, C _2-6 alkenyl, C _{2 - 6} alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^{b3 is} independently selected from -OR ^c3 , -NR ^c3 R ^c3 , halogen, -C(O)R ^c3 , -C(O)OR ^c3 , -C(O)NR ^c3 R ^c3 , -CN, -NHC(O)R ^c3 and -NHC(O)OR ^c3 ; Each R ^c3 independently of one another represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-6 ring Alkenyl, C _1-6 alkyl-OC _1-6 alkyl, (C _1-4 alkyl)HN-C _1-6 alkyl, (C _1-4 alkyl) ₂ NC _1-6 alkyl, a C _1-6 haloalkyl group, a 4 to 16 membered heterocycloalkyl group, and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group in the above group is optionally subjected to one or more of the same or different C _1-6 alkyl substituent; - (E0) X represents chlorine or fluorine; - wherein the compound (I) may also optionally their tautomers, racemates, Enantiomers, diastereomeric isomers or mixtures thereof or of the respective salt is present in all of the above forms.

In one aspect (A1) , the invention relates to compound (I) wherein R ² is selected from C _1-6 alkyl, C _1-4 alkoxy-C _1-4 alkyl, 5 to 6 members Heteroaryl, C _3-6 cycloalkyl, C _4-7 cycloalkylalkyl and phenyl are substituted by one or more halogens which may be the same or different.

In another aspect (A2) , the invention relates to compound (I) wherein R ² represents C _1-6 alkyl or phenyl, substituted by one or more halo of the same or different.

In another aspect (A3) , the invention relates to compound (I) wherein R ² represents C _1-6 alkyl.

In another aspect (A4) , the invention relates to compound (I) wherein R ² is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

In another aspect (A5) , the invention relates to compound (I) wherein R ² is selected from the group consisting of ethyl, n-propyl, isopropyl and isobutyl.

In another aspect (A6) , the invention relates to compound (I) wherein R ² is n-propyl.

In another aspect (A7) , the invention relates to compound (I) wherein R ² is a 5 to 6 membered heteroaryl group.

In another aspect (A8) , the invention relates to compound (I) wherein R ² is furyl or pyridyl.

In another aspect (A9) , the invention relates to compound (I) wherein R ² is furyl.

In another aspect (A10) , the invention relates to compound (I) wherein R ² is .

In another aspect (A11) , the invention relates to compound (I) wherein R ² is difluorophenyl.

In another aspect (B1) , the invention relates to compound (I) wherein R ³ is halogen.

In another aspect (B2) , the invention relates to compound (I) wherein R ³ is fluoro.

In another aspect (C1) , the invention relates to compound (I) wherein ring A is a nitrogen-containing 5 to 10 membered heteroaryl group.

In another aspect (C2) , the invention relates to compound (I) wherein ring A is a nitrogen-containing 5 to 6 membered heteroaryl group.

In another aspect (C3) , the invention relates to compound (I) wherein ring A is selected from the group consisting of pyridyl, pyrimidinyl and pyrazolyl.

In another aspect (C4) , the invention relates to compound (I) wherein ring A is pyridyl.

In another aspect (D1), the present invention relates to a compound (the I), wherein m represents 1; R ⁴ is a 3-11 heterocyclyl group, optionally substituted with one or more identical or different R ^a2 and / or R ^a2 each substituent R ^b2 independently of one another represent optionally substituted with one or more identical or different R ^b2 and / or substituted with a group of R ^c2, which is selected from C _1-6 alkyl, C _2-6 alkenyl a group, a C _2-6 alkynyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a C _4-6 cycloalkenyl group, and a 3 to 10 membered heterocyclic group; each R ^{b 2 is} independently selected from -OR ^C2 , -NR ^c2 R ^c2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC(O)R ^c2 and -NHC( O) OR ^c2 , and each R ^c2 independently of each other represent hydrogen or a group selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl a C _4-6 cycloalkenyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of halogen, C _1-6 alkyl and -C(O)-C _1-6 alkyl.

In another aspect (D2) , the invention relates to compound (I) wherein m represents 1; R ⁴ is a 4 to 7 membered nitrogen-containing heterocyclic group, optionally one or more of the same or different R ^a2 And/or R ^{b2 in} place of each R ^a2 independently of one another represent one or more groups substituted by the same or different R ^{b 2} and/or R ^{c 2} , which are selected from C _1-6 alkyl, C _{2− 6} alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^{b 2 is} independently selected from -OR ^c2 , -NR ^c2 R ^c2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC(O)R ^c2 and - NHC(O)OR ^c2 , and each R ^c2 independently of each other represent hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 ring An alkyl group, a C _4-6 cycloalkenyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents which may be the same or different selected from the group consisting of halogen, C _1-6 alkane And -C(O)-C _1-6 alkyl.

In another aspect (D3) , the invention relates to compound (I) wherein m represents 1; R ⁴ is selected from piperazinyl, piperidinyl and morpholinyl, all optionally by one or more The same or different R ^a2 and/or R ^b2 substitutions each R ^a2 independently of each other represent a group substituted with one or more identical or different R ^{b 2} and/or R ^{c 2 ,} optionally selected from C _1-6 An alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a C _4-6 cycloalkenyl group, and a 3 to 10 membered heterocyclic group; R ^{b2 is} independently selected from -OR ^c2 , -NR ^c2 R ^c2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC( O) R ^c2 and -NHC(O)OR ^c2 , and each R ^c2 independently of one another represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl a C _3-6 cycloalkyl group, a C _4-6 cycloalkenyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents which may be the same or different selected from the group consisting of halogen , C _1-6 alkyl and -C(O)-C _1-6 alkyl.

In the other aspect (D4) (D5) (D6) , the present invention relates to the compound (I) having the structural aspect (D1) (D2) (D3 ) , wherein each R ^a2 independently of each other represents a case Or a plurality of the same or different R ^b2 and/or R ^c2 substituted groups selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halo a C _3-6 cycloalkyl group and a 3 to 10 membered heterocyclic group; each R ^{b2 is} independently selected from the group consisting of -OR ^c2 , -NR ^c2 R ^c2 , halogen, -C(O)NR ^c2 R ^c2 and -CN, And each R ^c2 independently of each other represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl and 3 to 10 membered heterocyclic group, wherein the heterocyclic group is optionally subjected to one or A plurality of the same or different substituents selected from the group consisting of halogen, C _1-6 alkyl and -C(O)-C _1-6 alkyl.

In another aspect (D7) , the invention relates to compound (I) wherein m represents 1; R ⁴ is selected from -OR ^a3 and -NR ^a3 R ^a3 ; each R ^a3 independently represents hydrogen or, as appropriate a group substituted with one or more of the same or different R ^{b 3} and/or R ^c3 selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^{b3 is} independently selected from -OR ^c3 , -NR ^c3 R ^c3 , halogen, -C ( O) R ^c3 , -C(O)OR ^c3 , -C(O)NR ^c3 R ^c3 , -CN, -NHC(O)R ^c3 and -NHC(O)OR ^c3 ; each R ^c3 independently represents hydrogen Or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _1-6 alkane --OC _1-6 alkyl, (C _1-4 alkyl)HN-C _1-6 alkyl, (C _1-4 alkyl) ₂ NC _1-6 alkyl, C _1-6 haloalkyl, a 4- to 16-membered heterocycloalkyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group in the above group is optionally substituted by one or more of the same or different C _1-6 alkyl groups.

In another aspect (D8) , the invention relates to compound (I) wherein m represents 1, and R ⁴ is imidazolyl, optionally, one, two or three identical or different C _1-4 alkyl groups Replace.

In another aspect (D9) , the invention relates to compound (I) wherein m represents 0.

In another aspect (CD1) , the invention relates to compound (I) wherein m represents 1; R ⁴ and ring A together Wherein R ⁵ is C _1-6 alkyl.

In another aspect (CD2) , the invention relates to compound (I) wherein m represents 1, and R ⁴ and ring A together .

In another aspect (CD3) , the invention relates to compound (I) wherein m represents 1, and R ⁴ and ring A together Wherein R ⁶ is selected from the group consisting of fluorine, chlorine and bromine.

In another aspect (CD4) , the invention relates to compound (I) wherein m represents 1, and R ⁴ and ring A together Wherein R ⁷ is selected from the group consisting of C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-12 cycloalkylalkyl, 3 to 6 membered heterocyclic, -C ( O) C _1-6 alkyl and C _1-6 alkoxy-C _1-6 alkyl.

In another aspect (CD5) , the invention relates to compound (I) wherein m represents 1, and R ⁴ and ring A together Wherein R ⁷ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, C _4-12 cycloalkylalkyl, -C(O)C _1-6 alkyl, and C _1-6 alkoxy Base-C _1-6 alkyl.

In another aspect (E1) , the invention relates to compound (I) wherein X represents chlorine.

In another aspect (E2) , the invention relates to compound (I) wherein X represents fluorine.

All of the above structural aspects A1 to A11 , B1 and B2 , C1 to C4 , D1 to D9 , CD1 to CD5 , E1 and E2 are preferred embodiments of various aspects A0 , B0 , C0 , D0 , CD0 and E0 , respectively . Where CD0 represents a combination of C0 and D0 . With respect to the structural aspects A0 to A11 , B0 to B2 , C0 to C4 , D0 to D9 , CD0 to CD5 and E0 to E2 of the different molecular moieties of the compound (I) of the present invention, it is possible to arrange the combination ABCDE as needed to obtain a preferred one. Compound (I) . Each combination ABCDE represents and defines individual embodiments or general amounts of the compounds of the invention. Each individual embodiment or portion of the amount defined by this combination is also expressly included in the invention and is the subject of the invention.

The invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives and prodrugs of the compounds of formula (I) .

The invention further relates to pharmaceutically acceptable salts of the compounds of formula (I) with inorganic acids or bases or organic acids or bases.

In another aspect, the invention is directed to a compound of formula (I) (or a pharmaceutically acceptable salt thereof) as a medicament.

In another aspect, the invention relates to a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for use in a method of treating a human or animal body.

In another aspect, the invention relates to a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for use in the treatment and/or prevention of cancer, infection, inflammation, and autoimmune diseases.

In another aspect, the invention relates to a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for use in the treatment and/or prevention of cancer, infection, inflammation, and self in humans and animals In the method of immune disease.

In another aspect, the invention relates to the use of a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for the manufacture and/or prevention of cancer, infection, inflammation, and self A pharmaceutical composition for a body's immune disease.

In another aspect, the invention relates to a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for use in the treatment and/or prevention of cancer.

In another aspect, the invention relates to the use of a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for the manufacture of a pharmaceutical composition for the treatment and/or prevention of cancer.

In another aspect, the invention relates to a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for use in a method of treating and/or preventing cancer in a human or animal body.

In another aspect, the invention relates to a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for use in the treatment and/or prevention of colon cancer, melanoma, gallbladder cancer, and thyroid cancer .

In another aspect, the invention relates to the use of a compound of formula (I) (or a pharmaceutically acceptable salt thereof) for the preparation and/or prevention of colon cancer, melanoma, A pharmaceutical composition for gallbladder cancer and thyroid cancer.

In another aspect, the invention relates to a method of treating and/or preventing cancer, comprising administering to a human a therapeutically effective amount of a compound of formula (I) (or a pharmaceutically acceptable salt thereof) .

In another aspect, the invention relates to a pharmaceutical preparation comprising one or more compounds of the formula (I) (or a pharmaceutically acceptable salt thereof) as an active substance, optionally combining conventional excipients and/or Carrier.

In another aspect, the invention relates to a pharmaceutical preparation comprising a compound of formula (I) (or a pharmaceutically acceptable salt thereof) and at least one other cell inhibiting or cell different from formula (I) Toxic active substance.

definition

The terms that are not specifically defined herein are those that are apparent to those skilled in the art in light of the disclosure herein.

As used herein, unless otherwise stated, the following definitions apply: the use of the prefix C _xy (where x and y each represent a natural number ( x < y )) indicates a chain or ring structure or chain that is directly associated with and referred to and The combination of ring structures as a whole may consist of up to y and a minimum of x carbon atoms.

The indication of the number of members in a group containing one or more heteroatoms (heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) relates to the total atom of all ring members or chain members. The total number of or all ring and chain members.

The indication of the number of carbon atoms in the group consisting of a combination of a carbon chain and a carbocyclic structure (cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all carbocyclic and carbon chain members.

Alkyl represents a monovalent saturated hydrocarbon chain which may exist in the form of a straight chain (unbranched) and a branched chain. If the alkyl group is a substituted alkyl group, the substitutions can be carried out independently of one another in each case by mono- or poly-substitution on all carbon atoms bearing hydrogen.

The term " C _1-5 alkyl " includes, for example, H ₃ C-, H ₃ C-CH ₂ -, H ₃ C-CH ₂ -CH ₂ -, H ₃ C-CH(CH ₃ )-, H ₃ C- CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH(CH ₃ )- , H ₃ C-CH(CH ₃ )-CH ₂ -, H ₃ CC(CH ₃ ) ₂ -, H ₃ C-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH ₂ -CH(CH ₃ )-, H ₃ C-CH ₂ -CH(CH ₃ )-CH ₂ -, H ₃ C-CH(CH ₃ )-CH ₂ -CH ₂ -, H ₃ C-CH ₂ -C(CH ₃ ) ₂ -, H ₃ CC(CH ₃ ) ₂ -CH ₂ -, H ₃ C-CH ( CH ₃ )-CH(CH ₃ )- and H ₃ C-CH ₂ -CH(CH ₂ CH ₃ )-.

Other examples of alkyl groups are methyl (Me; -CH _3), ethyl _{(Et; -CH 2 CH 3)} , 1- propyl (n-propyl (n -propyl); n -Pr; -CH 2 CH ₂ CH _3), 2- propyl (i -Pr; isopropyl (iso -propyl); - CH ( CH 3) 2), 1- butyl (n-butyl (n -butyl); n -Bu; _{-CH 2 CH 2 CH 2 CH 3} ), 2- methyl-1-propyl (iso-butyl (iso -butyl); i -Bu; -CH 2 CH (CH 3) 2), 2- butyl ( sec-butyl (sec -butyl); sec -Bu; -CH (CH 3) CH 2 CH 3), 2- methyl-2-propyl (tert-butyl (tert -butyl); t -Bu; -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl; -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 3-methyl-1-butyl (isopentyl; -CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-2- Butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 2,2-dimethyl-1- Propyl (neopentyl; -CH ₂ C(CH ₃ ) ₃ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (n-hexyl; - CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl -2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4- Methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2 -methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), 2,3-dimethyl-1-butyl (-CH ₂ CH (CH _{3 )} CH(CH ₃ )CH ₃ ), 2,2-dimethyl-1-butyl (-CH ₂ C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3,3-dimethyl-1-butyl (-CH ₂ CH ₂ C(CH ₃ ) ₃ ), 2-methyl-1-pentyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-methyl-1-pentyl ( -CH ₂ CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl -1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2, 3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-indenyl (n-decyl); 1-indenyl (n-decyl) Wait.

Without further definition, the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl and the like mean saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms. .

If part of another group (composition) group (such as C _xy alkyl group or a C _xy alkyl group), the alkyl group of the above definition also applies.

The term alkylene may also be derived from an alkyl group . An alkyl group is divalent, different from an alkyl group and requires two binding partners. Formally, the second valence is produced by removing a hydrogen atom in the alkyl group . The corresponding groups are, for example, -CH ₃ and -CH ₂ -, -CH ₂ CH ₃ and -CH ₂ CH ₂ - or >CHCH ₃ and the like.

The term "C _1-4 alkylene" includes, for example, -(CH ₂ )-, -(CH ₂ -CH ₂ )-, -(CH(CH ₃ ))-, -(CH ₂ -CH ₂ -CH ₂ ) -, -(C(CH ₃ ) ₂ )-, -(CH(CH ₂ CH ₃ ))-, -(CH(CH ₃ )-CH ₂ )-, -(CH ₂ -CH(CH ₃ ))- , -(CH ₂ -CH ₂ -CH ₂ -CH ₂ )-, -(CH ₂ -CH ₂ -CH(CH ₃ ))-, -(CH(CH ₃ )-CH ₂ -CH ₂ )-, - (CH ₂ -CH(CH ₃ )-CH ₂ )-, -(CH ₂ -C(CH ₃ ) ₂ )-, -(C(CH ₃ ) ₂ -CH ₂ )-, -(CH(CH ₃ ) -CH(CH ₃ ))-, -(CH ₂ -CH(CH ₂ CH ₃ ))-, -(CH(CH ₂ CH ₃ )-CH ₂ )-, -(CH(CH ₂ CH ₂ CH ₃ ) )-, -(CHCH(CH ₃ ) ₂ )- and -C(CH ₃ )(CH ₂ CH ₃ )-.

Other examples of alkylene are methylene, ethyl stretching, stretch propyl, 1-ethyl stretched, stretch-butyl, 1-methyl-stretched propylene, 1,1-dimethyl ethyl stretch, 1,2-dimethylexylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1, 3-dimethyl-propyl, hexyl, and the like.

In the absence of further definition, the general terms of propyl, butyl, pentyl, hexyl and the like mean all possible isomeric forms having the corresponding number of carbon atoms, ie, the exopropyl group includes 1-methyl. The ethyl and butyl groups include 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and 1,2-dimethylethyl.

If a portion of another alkylene (composition) groups (e.g., HO-C _xy alkylene group or H ₂ NC _xy alkylene group), the above definition is also applicable to the alkylene group.

Unlike an alkyl group , an alkenyl group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a carbon-carbon double bond and one carbon atom can only be part of one carbon-carbon double bond. If an alkyl group having at least two carbon atoms as defined above is formally removed from two hydrogen atoms on adjacent carbon atoms and the free valence is saturated to form a second bond, the corresponding alkenyl group is formed.

Examples of alkenyl groups are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, butyl- 2-alkenyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1- Methyl-prop-1-enyl, 1-methylenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl -but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3- Alkenyl, hex-4-enyl, hex-5-alkenyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-Asia Methyl-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, pent-1,4 - a dienyl group, a pentane-1,3-dienyl group, a butane-1,3-dienyl group, a 2,3-dimethylbutyl-1,3-diene or the like.

In the absence of further definition, the general terms propylene, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl , decadienyl, decadienyl and the like mean all possible isomeric forms having the corresponding number of carbon atoms, that is, the propylene group includes prop-1-enyl and prop-2-enyl, and the butenyl group includes butyl- 1-alkenyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl and the like.

The alkenyl group may optionally be present in a cis or trans or E or Z orientation with respect to the double bond.

When the alkenyl group into another (composition) group (such as C _xy C _xy alkenyl group or alkenyloxy group) of the part, the above definition of alkenyl also applies.

Unlike an alkylene group , an alkenyl group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a carbon-carbon double bond and one carbon atom can only be a part of one carbon-carbon double bond. If in the alkylene group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, the corresponding alkenyl group is formed.

Examples of alkenyl groups are vinyl, propylene, 1-methylvinyl, butenyl, 1-methylpropenyl, 1,1-dimethylvinyl, 1,2- Dimethyl-extended vinyl, pentenyl, 1,1-dimethyl-propenyl, 2,2-dimethyl-propenyl, 1,2-dimethyl-propenyl, 1,3-di Methyl stretch propylene, hexenylene and the like.

In the absence of further definition, the general terms propylene, butenyl, pentenyl, hexenyl and the like mean all possible isomeric forms having the corresponding number of carbon atoms, ie exopropylene includes 1-methyl-vinyl extended and butenyl includes 1-methyl-propenyl, 2-methyl-propenyl, 1,1-dimethyl-vinyl and 1,2-dimethyl-vinyl .

The alkenyl group may be present in the cis or trans or E or Z orientation with respect to the double bond.

When the alkenyl group is part of another (combination) group (for example, in the HO-C _xy extended alkenylamino group or the H ₂ NC _xy stretching alkenyloxy group ), the above definition of the alkenyl group also applies. .

Unlike an alkyl group , an alkynyl group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by a carbon-carbon bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms in each case are formally removed and the free valence is saturated to form two other bonds, a corresponding Alkynyl .

Examples of alkynyl groups are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-propyl- 2-alkynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-yne A group, a hex-2-ynyl group, a hex-3-ynyl group, a hex-4-ynyl group, a hex-5-alkynyl group or the like.

Without further definition, the general terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, decynyl, decynyl and the like mean having the corresponding number of carbon atoms All possible isomeric forms, ie propyne The base includes a prop-1-ynyl group and a prop-2-ynyl group, and the butynyl group includes a but-1-ynyl group, a but-2-ynyl group, a but-3-ynyl group, and a 1-methyl-prop-1-yne group. Base, 1-methyl-prop-2-ynyl, and the like.

If the hydrocarbon chain bears at least one double bond and at least one reference bond, it is, by definition , a group of alkyne groups.

If the alkynyl group is part of another (combination) group (as for example in C _xy alkynylamino or C _xy alkynyloxy ), the above definition of alkynyl also applies.

Unlike an alkylene group , an alkynyl group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are bonded together by carbon-carbon bonding. Forming in the alkylene group having at least two carbon atoms as defined above, formally removing two hydrogen atoms on adjacent carbon atoms in each case and saturating the free valence to form two other bonds The corresponding alkynyl group .

Examples of an alkynyl group are an ethynyl group, a propynyl group, a 1-methyl ethynyl group, a butynyl group, a 1-methyl-propenyl group, a 1,1-dimethyl-exetylene group, 1, 2-dimethylexetylene, pentynylene, 1,1-dimethyl-propenyl, 2,2-dimethyl-propenyl, 1,2-dimethyl-propenyl, 1,3-Dimethyl-propenyl group, hexenylene group, and the like.

In the absence of further definition, the general terms for propynyl, butenyl, pentynyl, hexynyl and the like mean all possible isomeric forms of the corresponding number of carbon atoms, ie propyne The group includes a 1-methyl ethynyl group and the butynyl group includes a 1-methyl-propenyl group, a 2-methyl-propenyl group, a 1,1-dimethyl-exetylene group, and a 1,2-dimethyl group. Exoacetylene group.

If the alkynyl group is part of another (combination) group (for example, in the HO-C _xy alkynylamino group or the H ₂ NC _xy alkynyloxy group ), the above definition of the alkynyl group also applies. .

Heteroatoms mean oxygen, nitrogen and sulfur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is an alkyl ( alkenyl , alkynyl ) group as defined above by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another via the same or different halogen atoms. derivative. If the haloalkyl group (haloenyl, haloalkynyl) is further substituted, the substitutions can be carried out independently of one another in each case in the form of a mono- or poly-substituent on all carbon atoms bearing hydrogen.

Examples of haloalkyl ( haloenyl , haloalkynyl) are -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ CF ₃ , -CHFCF ₃ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CHFCH ₃ , -CF ₂ CF ₂ CF ₃ , -CF ₂ CH ₂ CH ₃ , -CF=CF ₂ , -CCl=CH ₂ , -CBr=CH ₂ , -C≡C-CF ₃ , -CHFCH ₂ CH ₃ , -CHFCH ₂ CF _3, etc.

The term haloalkyl (extended haloalkenyl, extended haloalkynyl ) is also derived from the haloalkyl (haloenyl, haloalkynyl) group previously defined. Unlike haloalkyl (haloenyl, haloalkynyl) , haloalkyl (extended haloalkenyl, extended haloalkynyl) is divalent and requires two binding partners. Formally, the second valence is formed by removing a hydrogen atom from a haloalkyl group (haloalkenyl group, haloalkynyl group) .

The corresponding groups are, for example, -CH ₂ F and -CHF-, -CHFCH ₂ F and -CHFCHF- or >CFCH ₂ F and the like.

The above definition also applies if the corresponding halogen-containing group is part of another (combination) group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl group a subgroup monocyclic hydrocarbon ring, bicyclic hydrocarbon rings and spiro hydrocarbon rings. The system is a saturated system. In a bicyclic hydrocarbon ring, the two rings are joined together such that they have at least two carbon atoms in common. In a spiro hydrocarbon ring, one carbon atom (spiro atom) belongs to two rings at the same time.

If the cycloalkyl group is substituted, the substitutions can be carried out independently of one another in each case in the form of a mono- or poly-substitution on all carbon atoms bearing hydrogen. The cycloalkyl group itself can be attached to the molecule as a substituent via each suitable position of the ring system.

Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl Bicyclo[2.2.2]octyl, bicyclo[4.3.0]decyl (octahydroindenyl), bicyclo[4.4.0]decyl (decalinyl), bicyclo[2.2.1]heptyl Bis), bicyclo [4.1.0] heptyl (norbornyl), bicyclo [3.1.1] heptyl (fluorenyl), spiro [2.5] octyl, spiro[3.3] heptyl, and the like.

If the cycloalkyl group is part of another (combination) group (such as, for example, in a C _xy cycloalkylamino group, a C _xy cycloalkyloxy group or a C _y cycloalkylalkyl group ), the above is a cycloalkyl group. The definition also applies.

If the free valence of the cycloalkyl group is saturated, an alicyclic group is obtained.

The term cycloalkyl can thus be derived from a previously defined cycloalkyl group . Unlike cycloalkyl groups , cycloalkylene groups are divalent and require two binding partners. Formally the second valence is obtained by removing a hydrogen atom from a cycloalkyl group . Corresponding groups are for example: cyclohexyl and or or (Extension of cyclohexyl).

If the extension is part of another cycloalkyl (composition) of a group (such as e.g. in the HO-C _xy alkyl group or a cycloalkyl extending H ₂ NC _xy extending cycloalkyl group), then extending above for cycloalkyl The definition also applies.

The cycloalkenyl group is also composed of a subgroup monocyclic hydrocarbon ring , a bicyclic hydrocarbon ring, and a spiro hydrocarbon ring . However, such systems are unsaturated systems, i.e., there is at least one carbon-carbon double bond, but no aromatic system. If a two hydrogen atom on an adjacent ring carbon atom is formally removed in a cycloalkyl group as defined above and the free valence is saturated to form a second bond, the corresponding cycloalkenyl group is obtained.

If the cycloalkenyl group is substituted, the substitutions can be carried out independently of one another in each case in the form of a mono- or poly-substitution on all carbon atoms bearing hydrogen. Cycloalkenyl group as a substituent may itself be linked to the molecule via a ring system of the position of each.

Examples of cycloalkenyl groups are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopentan-2 - alkenyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-ene , cycloheptan-3-enyl, cyclohept-4-enyl, cyclobutyl-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl , cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohex-1,5-dienyl, cyclohexan-2,4-dienyl, cyclohexa-1, 4-dienyl, cyclohex-2,5-dienyl, bicyclo[2.2.1]hept-2,5-dienyl -2,5-dienyl),bicyclo[2.2.1]hept-2-enyl Alkenyl), spiro[4,5]non-2-enyl and the like.

When the cycloalkenyl group is part of another (composition) of a group (e.g., C _xy e.g. in cycloalkenyl group, C _xy cycloalkenyl group or a cycloalkenyl group C _xy alkyl group), a cycloalkenyl group above with respect to The definition also applies.

If the free valence of the cycloalkenyl group is saturated, an unsaturated alicyclic group is obtained.

The term cycloalkenyl can thus be derived from a previously defined cycloalkenyl . Unlike cycloalkenyl , cycloalkenylene is divalent and requires two binding partners. Formally the second valence is obtained by removing a hydrogen atom from a cycloalkenyl group . Corresponding groups are, for example: cyclopentenyl and or or or (cyclopentenyl) and the like.

If the extension is part of another cycloalkenyl group (composition) of a group (such as e.g. in the HO-C _xy extending cycloalkenyl group or H ₂ NC _xy extending cycloalkenyl group), then extending above with respect to cycloalkenyl The definition also applies.

An aryl group means a monocyclic, bicyclic or tricyclic carbocyclic ring having at least one aromatic carbocyclic ring. It preferably represents a monocyclic group (phenyl) having 6 carbon atoms or a bicyclic group having 9 or 10 carbon atoms (two 6-membered rings or a 6-membered ring having a 5-membered ring), wherein The second ring may also be an aromatic ring, but may alternatively be a saturated or partially saturated ring.

If the aryl groups are substituted, the substitutions can be carried out independently of one another in each case in the form of mono- or poly-substituents on all carbon atoms bearing hydrogen. An aryl group as a substituent may itself be linked to the molecule via a ring system of the position of each.

Examples of aryl groups are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), anthracenyl, fluorenyl, phenanthryl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthalene). Base, naphthyl), dihydronaphthyl (1,2-dihydronaphthyl), anthracenyl and the like.

If another portion of aryl (composition) of a group (such as e.g. in the aryl group, aryl group or arylalkyl group), an aryl group of the above definitions also apply.

If the free valence of the aryl group is saturated, an aromatic group is obtained.

The term extended aryl can also be derived from a previously defined aryl group. Unlike aryl groups , the aryl group is divalent and requires two binding partners. Formally the second valence is formed by the removal of a hydrogen atom from the aryl group . Corresponding groups are for example: phenyl and or or (o-phenyl, meta-phenyl, para-phenyl), naphthyl and or or Wait.

The definitions above for aryl groups also apply if the aryl group is part of another (combination) group (for example, in the HO - exoarylamino group or the H ₂ N- extended aryloxy group ).

Heterocyclyl denotes a ring system which, from the previously defined cycloalkyl , cycloalkenyl and aryl groups , independently replaces one or more of the hydrocarbon rings via the groups -O-, -S- or -NH- The group -CH ₂ - or by substitution of one or more groups =CH- via a group =N-, wherein there may be no more than 5 heteroatoms in total, between two oxygen atoms and two sulfur atoms At least one carbon atom may be present between or between one oxygen atom and one sulfur atom, and the entire ring must be chemically stable. Heteroatoms may be present in all possible oxidation stages (sulfur → yttrium-SO-, 碸-SO ₂ -; nitrogen → N-oxide). In the heterocyclic group , no heteroaromatic ring is present, that is, no hetero atom is present as part of the aromatic system.

Directly derived from cycloalkyl , cycloalkenyl and aryl groups, the heterocyclic group consists of a subgroup of monocyclic heterocycles , bicyclic heterocycles , tricyclic heterocycles and spiroheterocycles , which may exist in saturated or unsaturated form.

Unsaturation means that at least one double bond is present in the ring system in question, but does not form a heteroaromatic system. In a bicyclic heterocycle, the two rings are linked together So that they have at least two (hetero) atoms in common. In the spiroheterocycle, one carbon atom (spiro atom) belongs to two rings at the same time.

If the heterocyclic group is substituted, the substitutions can be carried out independently of one another in each case in the form of a mono- or poly-substitution on all carbon and/or nitrogen atoms bearing hydrogen. Heterocyclic group as a substituent may itself be linked to the molecule via a ring system of the position of each.

Examples of heterocyclic groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, piperidinyl, piperazinyl, epoxy Alkyl, aziridine, azetidinyl, 1,4-dioxanyl, azepanyl, diazepine, morpholinyl, thiomorpholinyl, high? Polinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl- S -oxide, thiomorpholinyl- S , S -dioxide, 1,3-di Oxolyl, tetrahydropyranyl, tetrahydrothiopiperidyl, [1,4]-oxazepanyl, tetrahydrothiophenyl, homothiomorpholinyl- S , S- Dioxide, oxazolidinone, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuranyl, dihydropiperidyl, tetrahydrogen Thienyl- S -oxide, tetrahydrothiophenyl- S , S -dioxide, high thiomorpholino- S -oxide, 2,3-dihydroanthracene, 2 H -pyrrolyl, 4 H -piperidyl, 1,4-dihydropyridyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2- Oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1] octane , 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]decyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl, 1 -oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]decyl, 2 , 6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4.5]decyl, and the like.

Other examples are the structures shown below, which can be linked (hydrogen exchanged) via atoms each bearing hydrogen:

If the heterocyclic group is part of another (combination) group (for example, in a heterocyclic amino group, a heterocyclic oxy group or a heterocyclylalkyl group ), the above definition of the heterocyclic group also applies.

If the free valence of the heterocyclic group is saturated, a heterocyclic group is obtained.

The term extended heterocyclic group is also derived from a heterocyclic group as defined previously. Unlike heterocyclic groups , heterocyclic groups are divalent and require two binding partners. Formally the second valence is obtained by removing a hydrogen atom from a heterocyclic group . Corresponding groups are, for example, piperidinyl and or or , 2,3-dihydro-1 H -pyrrolyl and or or or Wait.

If the heterocyclic group is part of another (combination) group (for example, in the HO- extended heterocyclic amino group or the H ₂ N- extended heterocyclic oxy group), the above definition of the heterocyclic group is also Be applicable.

Heteroaryl denotes a monocyclic heteroaryl ring or a polycyclic ring having at least one heteroaromatic ring which, in addition to one or more carbon atoms, also contains one or more than the corresponding aryl or cycloalkyl (cycloalkenyl) group. The same or different heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein the resulting group must be chemically stable. Prerequisites for the presence of heteroaryl groups are heteroatoms and heteroaromatic systems.

If the heteroaryl group is substituted, the substitutions can be carried out independently of one another in each case in the form of mono- or poly-substituents on all carbon and/or nitrogen atoms bearing hydrogen. Heteroaryl itself as substituent may be linked to the molecule via a ring system in place of each of the (carbon and nitrogen).

Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl , thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl- N -oxide, pyrrolyl- N -oxide, pyrimidinyl- N -oxide, pyridazine -N -oxide, pyrazinyl- N -oxide, imidazolyl- N -oxide, isoxazolyl- N -oxide, oxazolyl- N -oxide, thiazolyl- N -oxide , oxadiazolyl- N -oxide, thiadiazolyl- N -oxide, triazolyl- N -oxide, tetrazolyl- N -oxide, sulfhydryl, isodecyl, benzo Furanyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, isoquinolyl, quinolyl, Quinoxalinyl, Polinyl, pyridazinyl, quinazolinyl, benzotriazinyl, pyridazinyl, oxazolopyridinyl, imidazopyridyl, Pyridyl, benzoxazolyl, pyridopyridyl, pyrimidinyl, fluorenyl, acridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl- N -oxide, Mercapto- N -oxide, isoquinolinyl- N -oxide, quinazolinyl- N -oxide, quinoxalinyl- N -oxide, pyridazinyl- N -oxide, pyridazine Base- N -oxide, carbazolyl- N -oxide, benzothiazolyl- N -oxide, benzimidazolyl- N -oxide, and the like.

Other examples are the structures shown below, which can be linked (hydrogen exchanged) via atoms each bearing hydrogen:

If the heteroaryl group is part of another (combination) group (such as, for example, in a heteroarylamino group, a heteroaryloxy group or a heteroarylalkyl group ), the above definition of heteroaryl group also applies.

If the free valence of the heteroaryl group is saturated, a heteroaromatic group is obtained.

The term heteroaryl is also derived from a heteroaryl group as previously defined. Unlike heteroaryls , heteroaryls are divalent and require two binding partners. Formally the second valence is obtained by removing a hydrogen atom from a heteroaryl group . Corresponding groups are for example: pyrrolyl and or or or Wait.

If the heteroaryl group is part of another (combination) group (for example, in the HO- extended heteroarylamino group or the H ₂ N- extended aryloxy group ), the above definition of the heteroaryl group is also Be applicable.

Substitution means that the hydrogen atom directly bonded to the atom under consideration is replaced by another atom or another group of atoms ( substituent ). Depending on the starting conditions (number of hydrogen atoms), mono- or poly-substitution can be carried out on one atom. If the substituent and the allowable valence of the atom to be substituted correspond to each other and the substitution results in a stable compound (ie, a compound which does not undergo rearrangement, cyclization or elimination of spontaneous conversion, for example), it is only possible to substitute with a specific substituent. .

A divalent substituent such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N ₂ or a similar substituent thereof may be only a substituent at a carbon atom, wherein the two The valence substituent = O may also be a substituent at the sulphur. In general, the substitution can be carried out only at the ring system by a divalent substituent and requires substitution by two hydrazine hydrogen atoms, i.e., a hydrogen atom of the same carbon atom saturated prior to the substitution. It is therefore possible to carry out the substitution by a divalent substituent only at the group -CH ₂ - or a sulfur atom of the ring system.

Stereochemistry/solvate/hydrate: Unless otherwise specified, the specified chemical formula or name shall encompass the tautomers and all stereoisomers, optical isomers and geometries throughout the specification and the accompanying claims. Isomers (eg, enantiomers, diastereomers, E / Z isomers, etc.) and racemates, as well as mixtures of different enantiomers in different ratios, diastereoisomers Mixtures of the body or a mixture of any of the above forms (in the presence of such isomers and enantiomers), and salts, including pharmaceutically acceptable salts thereof. The compounds and salts of the present invention may exist as unsolvated as well as solvates with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, in the context of the present invention, a solvate form such as a hydrate is considered equivalent to the unsolvated form.

Salt: The phrase " pharmaceutically acceptable " is used herein to mean that, in the context of sound medical judgment, it is suitable for contact with humans and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications. And matching the reasonable risk/benefit ratio to their compounds, substances, compositions and/or dosage forms.

As used herein, " pharmaceutically acceptable salts " refers to derivatives of the disclosed compounds wherein the parent compound is modified by the production of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like .

For example, such salts include acetate, ascorbate, benzene sulphonate, benzoate, besylate, bicarbonate, hydrogen tartrate, bromide/hydrobromide , ethylenediaminetetraacetate/ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride/hydrochloride, citrate, ethanedisulfonate, ethanedisulfonate, etolate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycollylars nilate, hexyl Hydroquinone salt, sulphate salt, hydroxy maleate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate , mandelate, methanesulfonate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, acid salt, naphthalene sulfonate, nitrate, oxalate, pamoate , pantothenate, phenylacetate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, hypoacetate, butyl Acid salt, sulfonium salt, sulfate, tannate, tartrate, teaclate, toluenesulfonate, triethiodide, ammonium salt, benzene Twin (benzathine), chloropro Chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, and procaine salt.

Other pharmaceutically acceptable salts can be formed from metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like (see also Pharmaceutical salts, Birge, SM et al, J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, the salts can be obtained by reacting the free acid or free base forms of such compounds with a suitable amount of a suitable base or acid in water or an organic diluent such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Prepared by reaction in or a mixture thereof.

For example, salts of acids other than the above-mentioned salts which are suitable for the purification or isolation of the compounds of the invention (e.g., trifluoroacetate) also form part of the invention.

Some abbreviations and their structural counterparts are listed below: -CH< or >CH- → =C< or >C= → -N= or =N- → >N- or -N< →

If, for example, in the sequence XYZ , component Y is considered to correspond to the structural part -N=, this means X = N- Z and X - N = Z.

In a statement such as the following: The dotted line means that the ring system can be attached to the molecule via carbon atoms 1 or 2 and is therefore equivalent to the following expression:

In a statement such as the following: or or The letter A has the function of ring naming to make it easier to indicate, for example, the connection of the ring in question to the other ring.

For the purpose of determining the adjacent group to which it is bound and the divalent group having the valence of the valence, for the purpose of illustration, the corresponding binding collocation is shown in parentheses if necessary, as in the following expression: Or (R ² )-C(O)NH- or (R ² )-NHC(O)-; the group or substituent is typically selected from a plurality of alternative groups/substituents having the corresponding group name (eg, R ^a , R ^b, etc.). If the group is used repeatedly to define different molecular moieties of the compounds of the invention, it must always be borne in mind that multiple uses are considered to be completely independent of each other.

For the purposes of the present invention, a therapeutically effective amount means an amount of a substance which is capable of avoiding the symptoms of the disease or preventing or slowing down such symptoms or prolonging the survival of the patient being treated.

Abbreviated list

The features and advantages of the present invention will be apparent from the following detailed description,

Preparation of the compounds of the invention summary

Unless otherwise stated, all reactions were carried out in commercially available equipment using methods commonly used in chemical laboratories. The starting material sensitive to air and/or moisture is stored under the protective gas and reacts with it and operates The protective gas (nitrogen or argon) is carried out.

The compounds of the invention were named using the Autonom software (Beilstein) according to the CAS rules.

The microwave reaction is carried out in a sealed vessel (preferably 2, 5 or 20 mL), preferably under agitation, in a starter/reactor manufactured by Biotage or a detector manufactured by CEM.

Chromatography

For preparative medium pressure chromatography (MPLC) , tannin made by Millipore (name: Granula Silica Si-60A 35-70 μm, NP phase) or C-18 RP-ruthenium (RP phase) manufactured by Macherey Nagel ( Name: Polygoprep 100-50 C18).

Automated normal phase chromatography was also performed using a CombiFlash Companion XL device and a CombiFlash Foxy 200 Dissolve Collector or a CombiFlash Companion Rf device manufactured by Isco. For this purpose, a commercially available RediSepRf (120 g silicone) one-way column was used. In addition, automated normal phase chromatography can also be performed using an Isolera rapid purification apparatus manufactured by Biotage. For this purpose, commercially available one-way SNAP cartridges (for example 50 g silicone) are used.

Thin layer chromatography was carried out on a ready-made silicone 60 TLC plate on a glass manufactured by Merck (with fluorescent indicator F-254).

Preparative high pressure chromatography (RP HPLC) of the exemplary compounds of the invention utilizes a column manufactured by Waters (name: XTerra Prep. MS C18, 5 μm, 30 x 100 mm or XTerra Prep. MS C18, 5 μm, 50 ×100 mm OBD or Symmetrie C18, 5 μm, 19×100 mm or Sunfire C18 OBD, 19×100 mm, 5 μm or Sunfire Prep C 10 μm OBD 50×150 mm or X-Bridge Prep C18 5 μm OBD 19×50 Mm or X-Bridge Prep C18 10 μm OBD 50×150 mm), Agilent-made pipe column (name: Zorbax SB-C8 5 μm PrepHT 21.2×50 mm) and pipe column manufactured by Phenomenex (name: Gemini C18 5 Μm AXIA 21.2×50 mm or Gemini C18 10 μm 50×150 mm). The compounds were dissolved using different gradients of H ₂ O/acetonitrile or H ₂ O/MeOH, with 0.1% HCOOH added to water (acidic conditions). For chromatography under alkaline conditions, a H ₂ O/acetonitrile gradient was also used, in which the water was made alkaline: 5 mL of NH ₄ HCO ₃ solution (158 g in 1 LH ₂ O solution) with H ₂ O ) and 2 mL of NH ₃ (7 M MeOH solution) to 1 L.

The normal phase preparative high pressure chromatography (NP HPLC) of the example compounds of the present invention utilizes a column (name: Nucleosil, 50-7, 40 x 250 mm) manufactured by Macherey & Nagel and a column manufactured by VDSoptilab (name : Kromasil 100 NH ₂ , 10 μM, 50 × 250 mm). Using different gradients of DCM / MeOH to eluting compound, which was added to 0.1% NH ₃ in MeOH.

Analytical HPLC (Reaction Control) of intermediate compounds using a column manufactured by Agilent (name: Zorbax SB-C8, 5 μm, 21.2×50 mm or Zorbax SB-C8 3.5 μm 2.1×50 mm) and manufactured by Phenomenex The column (name: Gemini C18 3 μm 2 × 30 mm) was used. The analysis device is also equipped with a quality detector in each case.

HPLC-mass spectrometry/UV spectrometry

The residence time/MS-ESI ⁺ characterizing the compound of the invention was generated using an HPLC-MS apparatus (high performance liquid chromatography with mass detector). Injection of the compound obtained in the retention time of the peak eluting _retentate is t = 0.00.

HPLC-MS Method A

HPLC: Agilent 1100 Series

MS: Agilent LC/MSD SL

Column: Waters, XBridge ^TM C18, 2.5 μm, 2.1 × 20 mm (part number 186003201)

Eluent: A: 0.1% NH ₃ (=pH 9-10) B: acetonitrile (HPLC grade)

Detection: MS: positive and negative mode

Quality range: 120-800 m/z

Flow rate: 1.00 mL/min

Column temperature: 60 ° C

Gradient: 0.00 min 5% B 0.00-2.50 min 5%→95% B 2.51-2.80 min 95% B 2.81-3.10 min 95%→5% B

The compounds of the invention are prepared by the synthetic methods described below, wherein the substituents of the formula have the meanings given above. These methods are intended to be illustrative of the invention, and do not limit the scope of the subject matter and the compounds claimed in the examples. Where the preparation of the starting compound is not described, it is commercially available or can be prepared analogously to the known compounds or methods described herein. The materials described in the literature were prepared according to the disclosed synthetic methods.

Scheme 1a: General synthetic route for compound (I)

The compound (I) of the present invention can be produced starting from a starting material SM-1 to SM-6 which is commercially available or can be synthesized as described below, by several methods as described in the general reaction scheme 1a.

Compound (I) can be synthesized via a copper-catalyzed [2+3] cycloaddition reaction of azide A-2 with a deprotected alkyne SM-5 . Azide A-2 can be obtained by the corresponding aniline A-1 as a starting material by diazotization with NaNO ₂ and formation of an azide with NaN ₃ in TFA. Amine A-1 is formed from a nitro compound SM-1 via a reduced nitro function, with sulfonium chloride or sulfonium chloride SM-6 to form a guanamine and subsequent removal of the amine functional group under, for example, aqueous HCl. To prepare.

According to another route, the compound (I) can be prepared from aniline B-6 and sulfonium chloride or sulfonium chloride SM-6 : aniline B-6 can be used as a starting material for the nitro compound SM-1 , and the protecting group is removed. Prepared by conversion to azide B-4 followed by cyclization to triazole B-5 and final reduction. Alternatively, aniline B-6 is prepared from the bromo compound B-2 by palladium-catalyzed amination with benzophenone imine, followed by removal of the protecting group under acidic conditions. The bromo compound B-2 is synthesized from the deprotected alkyne SM-5 and azide B-1 as a starting material via a copper-catalyzed [2+3] cycloaddition reaction, and the azide B-1 is again synthesized. It can be prepared from the amine compound SM-2 by diazotization followed by formation of an azide or by iodine compound SM-3 via copper catalysis to form an azide. In a third alternative, aniline B-6 is prepared from the corresponding benzoic acid B-3 via Curtius degradation. Benzoic acid B-3 can be prepared from the benzoate SM-4 via ester cleavage, copper catalyzed [2+3] cycloaddition reaction followed by ester cleavage.

The group R ¹ in the final compound (I) of the present invention as described in Scheme 1a has a structure

Directly synthesized following a synthetic route as described in Scheme 1a and with further modified functional groups in R ¹ or R ² (eg, halogen atoms, amine groups and hydroxyl groups (including cyclic amines), carboxylic acid or ester functional groups, The compound (I) of the nitrile or the like can be derivatized into other compounds by well-defined organic chemical conversion such as palladium-catalyzed cross-coupling, deuteration, guanidation, addition, reduction or (reductive) alkylation. (I) . These other steps are not described in Scheme 1a (but can be seen in Schemes 1b to 1e).

Likewise, other steps may be included in the synthetic route described in Scheme 1a, ie, may be derivatized with an intermediate compound.

In addition, it is also possible to use structural units with protecting groups, that is, other steps for removing the protecting groups are required.

Scheme 1b: Derivatization of Compound (I) of Species (I) ^a by Buchwald-Hartwig cross coupling reaction

Scheme 1c: Derivatization of compound (I) of species (I) ^c by deuteration

Scheme 1d: Derivatization of Compound (I) of Species (I) ^e by Alkylation

Scheme 1e: Derivatization of Compound (I) of Species (I) ^e by Reductive Amination

A. Synthesis of starting materials A. 1. Synthetic SM - 1 A.1.1. Experimental procedure for the synthesis of SM-1a

2,6-difluoro-acetanilide (4.00 g, 23.4 mmol) was dissolved in concentrated H ₂ SO ₄ (10 mL) and cooled to -10 ℃. KNO ₃ (4.73 g, 46.7 mmol) was added in small portions with stirring. After the addition was completed, the cooling bath was removed, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice water. The resulting precipitate was filtered off and dried in vacuo, to give SM-1a (HPLC-MS: t _retention = 0.50 min; MS (M + H) + = 215), which was used without further purification.

A.1.2. Experimental procedure for the synthesis of SM-1b

step 1

Was added to a solution of the 2-chloro-6-fluoro-aniline (24.8 g, 165 mmol) in _{HOAc (90 mL) Ac 2 O} (18 mL, 189 mmol) and stirred at 90 deg.] C for 1 hour. After cooling to room temperature, H ₂ O was added and the mixture was neutralized with a 2 M NaOH solution with stirring. The aqueous layer was extracted twice with DCM. And the solution was _washed with brine and half saturated NaHCO the organic layers were combined, dried over MgSO ₄ and evaporated to give the acetanilide, which was used without further purification.

Step 2

The acetanilide (31,0 g, 165 mmol) was dissolved in concentrated H ₂ SO ₄ (70 mL) and cooled to 0 ℃. Was added _{HNO 3 (11.4 mL, 166 mmol} ) and the mixture allowed to warm to room temperature overnight. H ₂ O was added slowly (cooled with ice) and the resulting mixture was extracted twice with DCM. _Washed with half-saturated brine solution and NaHCO the organic layers were combined, dried over MgSO ₄ and evaporated to give a mixture of SM-1b and of regioisomers. The crude material was recrystallized from MeCN to give pure SM-1b (HPLC-MS: t _retention = 0.56 min; MS (M + H) + = 233).

A. 2. Synthetic SM - 2 A.2.1. Experimental procedure for synthesizing SM-2a

step 1

2,6-Difluoro - acetanilide (3.02 g, 17.3 mmol) was dissolved in TFA (15 mL) and concentrated H (20 mL) in ₂ SO _4. NBS (3.20 g, 17.9 mmol) was added in small portions and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, and by the resulting precipitate was collected by filtration, washed with H ₂ O and dried in vacuo to afford bromide IM-1a (HPLC-MS: t _retention = 0.79 min; MS (M + H) + = 250/252), which was used without further purification.

Step 2

The bromide IM-1a (3.60 g, 14.4 mmol) was dissolved in EtOH (10 mL), concentrated hydrochloric acid (10 mL) was added and the mixture was stirred at 70 ° C for 18 hours. After cooling to room temperature, EtOH was evaporated, thus a precipitate formed which was collected by filtration and air dried to give aniline SM-2a (HPLC-MS: t _retention = 1.11 min; MS (M+H) ⁺ = 208/210 ), which was used without further purification.

A. 3. Synthetic SM - 5 Scheme 2: General synthetic route for alkynes of [2+3] cycloaddition

All alkynes described and utilized in the present invention for [2+3] cycloaddition are commercially available or can be cross-catalyzed via palladium catalyzed by the corresponding halogen precursor SM-7 as shown in Scheme 2 Coupling reaction (Sonogashira cross coupling reaction), followed by removal of the decyl protecting group with KF, K ₂ CO ₃ or TBAF or with aldehyde SM-8 as the starting material by the Bestmann-Ohira reaction Nitrophosphonate SM-9 was synthesized.

In fact, the reagents for [2+3] cycloaddition (alkynes which liberate or remove the protecting group) are usually produced in situ and directly converted to the corresponding triazole. However, in some cases, the decyl - protected alkyne SM-5 is deprotected and used in isolated form for [2+3] cycloaddition.

A.3.1. Experimental procedure for the synthesis of alkyne SM-5a

step 1

3-Fluoro-5-bromopyridine (998 mg, 5.50 mmol) and N -ethylpiperazine (1.9 mL, 14.7 mmol) were dissolved in n- BuOH (4 mL) and stirred at 100 ° C for 6 days. The reaction mixture was acidified with EtOAc (EtOAc)EtOAc. The aqueous layer was made basic and extracted 3 times with DCM. The organic layer was dried over MgSO ₄ merger, filtered and evaporated to give IM-2a (HPLC-MS: t _retention = 1.40 min; MS (M + H) + = 270), which was used without further purification.

Step 2

IM-2a (1.06 g, 3.52 mmol), CuI (60.9 mg, 0.32 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (55.5 mg, 0.08 mmol) were dissolved in N , N -diisopropylamine (2.0 mL) . TMS-acetylene (750 μL, 5.31 mmol) was added and the mixture was stirred at 100 ° C for 30 minutes. After cooling to room temperature, the pH was adjusted to pH 4 with 8 N hydrochloric acid. The reaction mixture was three times extracted with DCM and the combined organic layer is MgSO ₄ dried over merger, filtered and evaporated to give SM-5a (HPLC-MS: t _retention = 2.00 min; MS (M + H) + = 288), which does not Used after further purification.

A.3.2. Experimental procedure for the synthesis of alkyne SM-5b

3-Bromo-5-methoxy-pyridine (1.15 g, 6.09 mmol), CuI (29.0 mg, 0.15 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (107 mg, 0.15 mmol) in N under N atmosphere TMS-acetylene (947 μL, 6.70 mmol) was added to a suspension of N -diisopropylamine (2.6 mL) and the mixture was stirred at 70 ° C for 1 hour. After re-cooling, MeCN was added, the mixture was filtered and evaporated. The residue was dissolved in HCl (1 N) and extracted 3× with DCM. Dried over Na ₂ SO ₄ the combined organic layers were, filtered and evaporated. The residue was purified by Kugelrohr distillation to give SM-5b (HPLC-MS: t _retention = 2.21 min; MS (M+H) ⁺ = 206).

A.3.3. Experimental procedure for the synthesis of alkyne SM-5c

2-Chloro-5-iodo-pyrimidine (513 mg, 2.14 mmol), CuI (13.3 mg, 0.07 mmol) and (PPh ₃ ) ₂ PdCl ₂ (40.7 mg, 0.06 mmol) were dissolved in anhydrous THF (10 mL) . NEt ₃ (0.57 mL, 4.05 mmol) and TMS- acetylene (0.42 mL, 2.91 mmol) were added and the mixture was stirred at 50 ° C overnight. The mixture was diluted with THF, filtered through celite ^TM and evaporated. The residue was dissolved in water and extracted with EtOAc EtOAc. The organic layer was dried over MgSO ₄ merger, filtered and evaporated. The residue IM-3a (HPLC-MS: t _retention = 2.06 min; MS (M + H) + = 211) was used without further purification.

IM-3a (400 mg, 1.90 mmol) was dissolved in MeCN (6 mL). Add 1-(2-methoxy-ethyl)-piperidin-4-yl-amine (474 mg, 2.99 mmol) and DIPEA (0.5 mL, 2.93 mmol), seal the vial and warm to 60 ° C overnight until LC - MS indicates complete conversion. The reaction mixture containing SM-5c (HPLC-MS: t _retention = 1.99 min; MS (M+H) ⁺ = 333) was used directly in the next step (removing the protecting group and the cycloaddition reaction).

A.3.4. Experimental procedure for the synthesis of alkyne SM-5d

step 1

To a solution of 4-methyl- 1H -imidazole (186 mg, 2.27 mmol) in EtOAc (3 mL) EtOAc. 3-bromo-5-fluoro-pyridine (208 mg, 1.18 mmol) was added and the mixture was heated at 100 ° C for 3 h. H ₂ O was added, the mixture was adjusted to pH 10 with NaOH solution (2 N) and extracted 3 times with DCM. The organic layer is MgSO ₄ dried over merger, filtered and evaporated to give IM-2b (HPLC-MS: t _retention = 0.89 min; MS (M + H) + = 238/240), which was used without further purification.

Step 2

IM-2b (280 mg, 1.18 mmol), CuI (25.2 mg, 0.13 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (41.7 mg, 0.06 mmol) were dissolved in N , N -diisopropylamine (1.7 mL) . TMS-acetylene (332 μL, 2.35 mmol) was added and the mixture was stirred at 60 ° C overnight. After cooling to room temperature, DCM was added and the organic phase was extracted twice with 1N hydrochloric acid. The combined aqueous layers were adjusted to pH 10 with 1 N NaOH solution and extracted three times with DCM. The combined organic layers were filtered, dried over Na ₂ SO _4, then filtered and evaporated to give SM-5d, which was used without further purification. SM-5d can optionally be purified by RP HPLC to eliminate minor amounts of the imidazole regioisomer formed during the nucleophilic substitution reaction.

A.3.5. Experimental procedure for the synthesis of alkyne SM-5e

step 1

To a solution of tetrahydro- 4H -piperidin-4-ol (534 mg, 5.23 mmol) in THF (5 mL), EtOAc. 3-Bromo-5-fluoro-pyridine (922 mg, 5.24 mmol) was added and the mixture was stirred at room temperature overnight. H ₂ O was added and the reaction mixture was extracted three times with EtOAc. The organic layer is MgSO ₄ dried over merger, filtered and evaporated to give IM-2c (HPLC-MS: t _retention = 1.07 min; MS (M + H) + = 258/260), which was used without further purification.

Step 2

Add N , N - II to a solution of IM-2c (600 mg, 2.32 mmol), CuI (19.2 mg, 0.10 mmol) and Pd(dppf)Cl ₂ (63.4 mg, 0.08 mmol) in THF (4 mL) Isopropylamine (2.5 mL) and after 5 minutes, TMS-acetylene (750 μL, 5.35 mmol) was added under an inert atmosphere. The resulting mixture was stirred at 90 ° C for 16 hours. The reaction mixture was filtered and SM-5e was used as a solution in the next step.

A.3.6. Experimental procedure for the synthesis of alkyne SM-5f

step 1

Add K (7 mL) in a solution of pyridine (198 mg, 1.71 mmol) in DMF _{2 CO 3 (335 mg, 2.44} mmol) and the mixture was stirred at 50 ℃ 72 Hours - 3-bromo-5-hydroxy. The reaction mixture was filtered and purified by RP MPLC. The fractions containing the product were pooled, the MeCN was evaporated and the aqueous residue was extracted 3 times with DCM. The organic layer was dried over MgSO ₄ merger, filtered and evaporated to give IM-2d (HPLC-MS: t _retention = 0.95 min; MS (M + H) + = 232/234).

Step 2

Add N , N - II to a solution of IM-2d (100 mg, 0.43 mmol), CuI (4.70 mg, 0.03 mmol) and Pd(dppf)Cl ₂ (13.0 mg, 0.02 mmol) in THF (3 mL) Isopropylamine (550 μL) and after 5 minutes, TMS-acetylene (125 μL, 0.89 mmol) was added under an inert atmosphere. The resulting mixture was stirred at 90 ° C for 16 hours. The reaction mixture was filtered and SM-5f was used as a solution in the next step.

A.3.7. Experimental procedure for the synthesis of alkyne SM-5g

step 1

Add KOtBu (1.91 g, 17.0 mmol) to a solution of 2-( N -methyl- N -isopropylamino)-ethanol (2.00 g, 11.4 mmol) in THF (10 mL) The mixture was stirred for 20 minutes. 3-Bromo-5-fluoro-pyridine (2.00 g, 11.4 mmol) was added and the mixture was stirred at room temperature overnight. H ₂ O was added and the reaction mixture was extracted three times with EtOAc. The organic layer was dried over MgSO ₄ merger, filtered and evaporated to give IM-2e, which was used without further purification.

Step 2

IM-2e (3.10 g, 11.4 mmol) was dissolved in EtOAc (20 mL). Add NEt ₃ (13 mL), CuI (64.8 mg, 0.34 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (239 mg, 0.34 mmol) and TBDMS-acetylene (4.0 mL, 28.4 mmol) and stir the mixture at 60 ° C 5 hours. The reaction mixture was diluted with EtOAc, filtered and evaporated. The residue was dissolved in DCM and purified by flash chromatography using DCM/MeOH (9:1) as solvent. The fractions of the product containing SM-5g were evaporated (HPLC-MS: t _retention = 2.45 min; MS (M+H) ⁺ = 333).

Similar to the procedures described in A.3.1. to A.3.7. above, other alkyne SM-5s can be prepared using various amine, bromo or iodoaryl and decyl protected acetylenes. Most of the alkyne can be used without further purification. To obtain higher purity decyl protected alkyne, Coogare® distillation or flash chromatography can be used using different gradients of cyclohexane/EtOAc as the leaching agent.

B. Synthesis of compound (I) with SM-1 as starting material B. 1. Synthesis of aniline A - 1 B.1.1. Experimental procedure for the synthesis of aniline A-1a

step 1

SM-1a (55.0 g, 254 mmol) was dissolved in MeOH (1.0 L). Pd/C (10.0 g, 10%) was added and the mixture was hydrogenated in an autoclave at 200 psi for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by hydrazine gel column chromatography using DCM / MeOH (96: 4) as solvent. The fractions of the product containing the aniline intermediate were combined and evaporated (HPLC-MS: t _retention = 0.25 min; MS (MH) ^- = 185).

Step 2

Add n-propanesulfonium chloride SM-6a (29.5 mL, 263 mmol) to a solution of the aniline intermediate (35.0 g, 188 mmol) in EtOAc (EtOAc) The mixture was stirred for 16 hours. The reaction mixture was diluted with EtOAc (200 mL) and then evaporated. The organic layer was washed with water and hydrochloric acid (1 N), dried over MgSO ₄ and evaporated to give IM-4a, which was used without further purification.

Step 3

The IM-4a (38.0 g, 130 mmol) was dissolved in _{EtOH (250 mL), H 2} O (200 mL) and concentrated hydrochloric acid (200 mL) and heated to 80 deg.] C for 2 hours. The reaction mixture was concentrated under reduced pressure and aqueous EtOAc (4 N) was evaporated. , Washed with saturated NaCl solution and dried by the combined organic layers over MgSO _4, filtered and evaporated to give the hydrochloride form A-1a (HPLC-MS: t _retention = 0.22 min; MS (MH) - = 249), It was used without further purification.

B.1.2. Experimental procedure for the synthesis of aniline A-1d

step 1

Add _{NH 4 Cl (1.77 g, 33.1} mmol) solution in 40 mL H ₂ O in the direction of the SM-1b (14.9 g, 64.0 mmol) in EtOH (450 mL) solution, and the mixture was stirred at 70 ℃. Iron powder (18.0 g, 322 mmol) was added in small portions and the mixture was stirred at 70 ° C for 20 hours. After cooling to room temperature, EtOH was evaporated, the residue was dissolved in EtOAc, washed with H ₂ O and brine, dried over Na ₂ SO _4, filtered and evaporated to give the aniline, which was used without further purification.

Step 2

Add SM-6b (2.03 g, 11.8 mmol) and pyridine (1.8 mL) and the mixture was stirred at room temperature for 3 days aniline (1.80 g, 8.88 mmol) in DCM (85 mL) in the solution. DCM was added and washed with half-saturated KHSO ₄ solution and the resulting mixture was washed with brine, dried over MgSO _4, filtered and evaporated. The crude material was adsorbed onto silica gel and purified by flash chromatography using DCM/MeOH gradient. The fractions of the product containing IM-4b were evaporated (HPLC-MS: t _retention = 0.00 min; MS (M+H) ⁺ = 333).

Step 3

To a solution of IM-4b (2.30 g, 6.91 mmol) in EtOAc (EtOAc) After cooling to room temperature, EtOH was evaporated, the residue aqueous solution was neutralized with 4 M NaOH to pH 6 and then extracted twice with DCM. , Dried with brine the combined organic layers over Na ₂ SO _4, filtered and evaporated. The residue was dissolved in MeCN / H ₂ O and freeze-dried in to give the A-1d, which was used without further purification.

Similar to the above procedure, other aniline A-1 can be prepared using various sulfonium chloride SM-6 (other nitro compounds SM-1 are also used).

B. 2. Synthesis of azide A - 2 B.2.1. Experimental procedure for the synthesis of azide A-2a

In TFA (4 mL) in small portions to the solution of aniline was added to the A-1a (502 mg, 2.00 mmol) at _{0 ℃ NaNO 2 (277 mg,} 4.02 mmol) and the mixture was stirred for 30 min. NaN ₃ (1.33 g, 20.2 mmol) was added and stirring was continued for a further 15 min. The reaction mixture was diluted dropwise with Et ₂ O and stirred for 1 hour. Water was added and the mixture was extracted 3 times with Et ₂ O. The organic layer was dried over MgSO ₄ merger, filtered and concentrated in vacuo to afford A-2a (HPLC-MS: t _retention = 0.78 min; MS (MH) - = 275), which was used without further purification.

B.2.2. Experimental procedure for the synthesis of azide A-2d

Add NaNO ₂ (316 mg, 4.58 mmol) in small portions to a solution of aniline A-1d (1.11 g, 3.82 mmol) in TFA (4 mL) at -10 ° C and stir the mixture below -5 ° C 15 minutes. Was added _{NaN 3 (380 mg, 5.79 mmol} ) and stirring was continued for 60 minutes. The reaction mixture was diluted dropwise with Et ₂ O and stirred for 1 hour. Water was added and the mixture was extracted twice with DCM. , Dried and washed with half saturated NaHCO ₃ and with brine combined organic layers were over MgSO _4, filtered and concentrated in vacuo to afford A-2d (HPLC-MS: t _retention = 0.84 min; MS (MH) - = 315), which does not Used after further purification.

Similar to the above procedure, other azide A-2 can be prepared using aniline A-1 .

B. 3. Synthesis of the final compound (I) B.3.1. Experimental procedure for synthesis example I-1

To a solution of the TMS-protected alkyne SM-5a (153 mg, 0.53 mmol) in MeOH (5 mL) EtOAc. Add azide A-2a (111 mg, 0.40 mmol) to the reaction mixture, followed by sodium ascorbate (250 μL, 1 M aqueous solution, 0.25 mmol) and CuSO ₄ (20 μL, 1 MH ₂ O solution, 0.02 mmol) ). The resulting mixture was stirred at 45 ° C for 16 hours. The solvent was removed in vacuo, the residue was dissolved in H ₂ O and extracted 2 times with EtOAc. The organic layer was dried over MgSO ₄ merger, filtered and evaporated. The residue was dissolved in DMF / H ₂ O /MeCN and purified by EtOAc. The fractions of the product containing lyophilized I-1 were lyophilized (HPLC-MS: t _retention = 1.15 min; MS (M+H) ⁺ = 492).

B.3.2. Synthesis of the experimental program of Example I-2

To a solution of the TMS-protected alkyne SM-5b (110 mg, 0.54 mmol) in MeOH (5 mL) EtOAc. Add azide A-2a (102 mg, 0.37 mmol) to the reaction mixture, followed by sodium ascorbate (250 μL, 1 M aqueous solution, 0.25 mmol) and CuSO ₄ (20 μL, 1 MH ₂ O solution, 0.02 mmol) The resulting mixture was stirred at 45 ° C for 16 hours. The solvent was removed in vacuo, the residue was dissolved in H ₂ O and extracted 2 times with EtOAc. The organic layer was dried over MgSO ₄ merger, filtered and evaporated. The residue was dissolved in DMF / H ₂ O /MeCN and purified by EtOAc. The fractions of the product containing lyophilized I-2 (HPLC-MS: t _retention = 1.05 min; MS (M+H) ⁺ = 410).

B.3.3. Synthesis of the experimental program of Example I-3

TMS protected alkyne SM-5h (213 mg, 0.64 mmol), KF (48.2 mg, 0.83 mmol) was added sequentially to a solution of azide A-2a (155 mg, 0.56 mmol) in MeOH (5 mL) , sodium ascorbate (83.4 mg, 0.42 mmol) and _{CuSO 4 (13.5 μL, 0.8 MH} 2 O solution, 0.01 mmol) and the resulting mixture was stirred for 16 hours at 40 ℃. The solvent was evaporated and the residue was taken in EtOAc EtOAc. The fractions containing the product of lyophilized I-3 (HPLC-MS: t _retention = 1.17 min; MS (M+H) ⁺ = 536).

B.3.4. Synthesis of the experimental program of Example I-4

TMS protected alkyne SM-5w (106 mg, 0.56 mmol), KF (66.0 mg, 1.14 mmol) was added sequentially to a solution of azide A-2a (152 mg, 0.55 mmol) in MeOH (5 mL) Ascorbic acid Na (79.6 mg, 0.40 mmol) and CuSO ₄ (13.6 μL, 0.8 MH ₂ O solution, 0.01 mmol) and the mixture was stirred at 40 ° C for 16 hours. The solvent was evaporated and the residue was taken in EtOAc EtOAc. The fractions containing the product of lyophilized I-4 (HPLC-MS: t _retention = 0.00 min; MS (M+H) ⁺ = 394).

B.3.5. Experimental procedure for the synthesis of I-5

A solution of the alkyne SM-5x (96.3 mg, 0.82 mmol, removed from K ₂ CO ₃ ) was added sequentially to a solution of azide A-2a (199 mg, 0.72 mmol) in MeOH (10 mL). Protective group), sodium ascorbate (107 mg, 0.54 mmol) and CuSO ₄ (36.2 μL, 0.8 MH ₂ O solution, 0.03 mmol). The resulting mixture was stirred at 40 ° C for 3 days. The solvent was evaporated and the residue was taken in EtOAc EtOAc. The fractions containing the product of lyophilization of I-5 were lyophilized (HPLC-MS: t _retention = 0.86 min; MS (M+H) ⁺ = 395).

B.3.6. Experimental procedure for the synthesis of I-6

Was added to I-5 (80.0 mg, 0.20 mmol) in Ac (3 mL) solution of the ₂ O in NaOAc (26.5 mg, 0.32 mmol) and the mixture was refluxed for 2 hours to obtain triple acetylation product. After re-cooling, H ₂ O and NaHCO ₃ solutions were added and the mixture was extracted 3 times with DCM. The organic layer was dried over MgSO ₄ merger, filtered and evaporated. The residue was dissolved in MeOH (3 mL) EtOAc (EtOAc) HCl (1 N, 1 mL) was added and solvent was evaporated. The residue was dissolved in aliquots of DMF and purified by EtOAc. The fractions containing the product of lyophilized I-6 (HPLC-MS: t _retention = 0.95 min; MS (M+H) ⁺ = 437).

B.3.7. Experimental procedure for the synthesis of I-7

To a solution of the TMS-protected alkyne SM-5y (4.40 g, 17.3 mmol) in MeOH (EtOAc) (EtOAc) Azide A-2a (4.78 g, 17.3 mmol) was added to the reaction mixture, after the addition of sodium ascorbate (685 mg, 3.46 mmol) and _{CuSO 4 (4.3 mL, 0.8 MH} 2 O solution, 3.46 mmol) and 45 The resulting mixture was stirred at ° C for 3 days. The solvent was removed in vacuo, the residue was dissolved in H ₂ O and extracted three times with DCM. The organic layer was dried over MgSO ₄ merger, filtered and evaporated. The residue was recrystallized from MeCN to afford I-7 (HPLC-MS: t _retention = 0.96 min; MS (M + H) + = 458/460). Substances of higher purity can be obtained by gel chromatography using a cyclohexane/EtOAc gradient.

B.3.8. Experimental procedure for the synthesis of I-8

To an I-7 (100 mg, 0.22 mmol), 4-piperidin-4-yl-morpholine (44.6 mg, 0.26 mmol), Pd ₂ (dba) ₃ (20.0 mg, 0.02 mmol), To the di-tert-butylphosphine (13.2 mg, 0.04 mmol) and NaOtBu (86.5 mg, 0.87 mmol) were added 1,4-dioxane (2.5 mL). The mixture was stirred at 100 ° C for 6 hours and evaporated. The residue was dissolved in H ₂ O and EtOAc and the aqueous layer was extracted three times with DCM. The organic layer was dried over MgSO ₄ merger, filtered and evaporated. The residue was taken up in EtOAc / EtOAc (EtOAc) The fractions containing the product of I-8 were evaporated (HPLC-MS: t _retention = 0.88 min; MS (M+H) ⁺ = 548), dissolved in MeCN/H ₂ O and lyophilized.

B.3.9. Experimental procedure for the synthesis of I-33

Add MeOH (9 mL) and KF (452 mg, 7.78 mmol) to the filtered reaction solution of SM-5e (636 mg [yield of theory yield], 2.31 mmol) from previous step (A.3.5.) and at 45 The mixture was stirred at ° C for 16 hours. A-2a (287 mg, 1.04 mmol), sodium ascorbate (180 μL, 1 M aqueous solution, 0.18 mmol) and CuSO ₄ (120 μL, 1 M aqueous solution, 0.12 mmol) were added and the mixture was stirred for 24 hours. The solvent was evaporated, the residue was dissolved in H ₂ O and extracted 3 times with EtOAc. The combined organic layers were evaporated and the residue was crystalljjjjjjj The fractions containing the product of lyophilized I-33 (HPLC-MS: t _retention = 0.88 min; MS (M+H) ⁺ = 480).

B.3.10. Experimental procedure for the synthesis of I-48

2,4-Dimethylimidazole (228 mg, 2.30 mmol), 3,4,7,8-tetramethyl was added sequentially to a solution of I-7 (100 mg, 0.22 mmol) in DMF (3.0 mL) -1,10-morpholine (52.0 mg, 0.22 mmol), CuI (64.0 mg, 0.34 mmol) and Cs ₂ CO ₃ (198 mg, 0.60 mmol) and stirred at 105 ° C under inert atmosphere (Ar) 2 days. After cooling to room temperature, MeCN (25 mL) was added, the mixture was filtered and the filtrate was reduced in vacuo. A small amount of H ₂ O and a few drops of formic acid were added to the residue and the mixture was purified twice by RP HPLC. The fractions of the product containing lyophilized I-48 (HPLC-MS: t _retention = 0.87 min; MS (M+H) ⁺ = 474).

B.3.11. Experimental procedure for the synthesis of I-49 and I-50

step 1

To a solution of the TMS-protected alkyne SM-5t (3.46 g, 9.62 mmol) in MeOH (EtOAc) Add azide A-2a (1.26 g, 8.16 mmol), sodium ascorbate (500 μL, 1.0 MH ₂ O solution, 500 mmol) and CuSO ₄ (200 μL, 1.0 MH ₂ O solution, 200 mmol) at 45 The resulting mixture was stirred at ° C for 16 hours. The solvent was evaporated, and the residue was dissolved in H ₂ O and extracted 3 times with EtOAc. , Dried and washed with brine combined organic layers were over MgSO _4, filtered and evaporated to afford I-49 (HPLC-MS: t _retention = 1.09 min; MS (M + H) + = 564), which was used without further purification use.

Step 2

I-49 (4.61 g, 8.18 mmol) was dissolved in 1,4-dioxane (40 mL) and concentrated hydrochloric acid (1.0 mL). The solvent was removed in vacuo, the residue was dissolved in H ₂ O and the pH is adjusted. The mixture was extracted twice with EtOAc at pH 4 and pH 8. The combined organic layers were evaporated, the dissolved in MeCN / H ₂ O and freeze-dried in, to give I-50 (HPLC-MS: t _retention = 0.87 min; MS (M + H) + = 464). To increase the yield of I-50 , the aqueous phase was lyophilized and the residue was purified by RP HPLC.

B.3.12. Experimental procedure for the synthesis of I-51

I-50 (152 mg, 0.33 mmol) was dissolved in DMF (3 mL) and 3- oxetane (69.0 mg, 0.96 mmol) and HOAc (20 μL) was added and the mixture was shaken for 1 min. NaBH(OAc) ₃ (349 mg, 1.65 mmol) was added and the mixture was stirred at room temperature for 18 hr. H ₂ O was added and the mixture was purified by RP HPLC. The fractions containing the product of lyophilized I-51 (HPLC-MS: t _retention = 0.83 min; MS (M+H) ⁺ = 520).

B.3.13. Experimental procedure for the synthesis of I-52

The I-50 (149 mg, 0.32 mmol) was dissolved in DMF (5 mL), was added _{K 2 CO 3 (75.1 mg,} 0.54 mmol) and the mixture was stirred for 10 minutes. Bromoacetonitrile (72.5 mg, 0.59 mmol) was added and the mixture was stirred at 50 ° C for 72 hours. After cooling to room temperature, 1 N HCl was added and the mixture was filtered and purified by RP HPLC and then EtOAc. The fractions containing the product of I-52 were evaporated (HPLC-MS: t _retention = 0.99 min; MS (M+H) ⁺ = 503), dissolved in H ₂ O/MeCN and lyophilized.

B.3.14. Experimental procedure for the synthesis of I-53

I-50 (155 mg, 0.33 mmol) was dissolved in DMF (5 mL), K ₂ CO ₃ (75.7 mg, 0.55 mmol) was added and the mixture was stirred for 10 min. Bromopropyne (in 80% toluene solution; 74.4 mg, 0.50 mmol) was added and the mixture was stirred at 50 ° C for 72 hours. After cooling to room temperature, 1 N HCl was added and the mixture was filtered and purified sequentially by RP HPLC and NP HPLC. The fractions containing the product of I-53 were evaporated (HPLC-MS: t _retention = 1.05 min; MS (M+H) ⁺ = 502), dissolved in H ₂ O/MeCN and lyophilized.

B.3.15. Experimental procedure for synthesis example I-54

Add TMS protected alkyne SM-5j (103 mg, 0.33 mmol), KF (30.0 mg, 0.51 mmol) to a solution of azide A-2d (100 mg, 0.32 mmol) in MeOH (3 mL) H ₂ O (500 μL), sodium ascorbate (33.0 mg, 0.17 mmol) and CuSO ₄ (6.00 mg, 0.04 mmol) and the mixture was stirred at room temperature for 20 hr. The reaction mixture was diluted with MeCN (2 mL) filtered and purified by EtOAc. The fractions containing the product of lyophilized I-54 (HPLC-MS: t _retention = 0.95 min; MS (M+H) ⁺ = 558).

B.3.16. Experimental procedure for synthesis example I-55

TMS-protected alkyne SM-5b (71.0 mg, 0.35 mmol), KF (30.0 mg, 0.51 mmol) was added sequentially to a solution of azide A-2d (100 mg, 0.32 mmol) in MeOH (3 mL) H ₂ O (500 μL), sodium ascorbate (32.0 mg, 0.16 mmol) and CuSO ₄ (5.00 mg, 0.03 mmol) and the mixture was stirred at room temperature for 20 hr. The resulting precipitate was filtered, washed with H ₂ O and cold MeCN and air dried. The material was dissolved in MeCN / H ₂ O and freeze-dried in, to give I-55 (HPLC-MS: t _retention = 0.80 min; MS (M + H) + = 450).

Similar to the above procedures B.3.1. to B.3.16., other final compounds were prepared using other azide A-2 and a decyl protected alkynes SM-5 .

C. Synthesis of Compound (I) with SM-2 as Starting Material C. 1. Synthesis of azide B - 1 C.1.1. Experimental procedure for synthesizing B1-a

The aniline SM-2a (2.66 g, 12.8 mmol) was suspended in TFA (60 mL) and cooled to 0. NaNO ₂ (1.39 g, 20.1 mmol) was added and the mixture was stirred 30 min. NaN ₃ (1.06 g, 16.2 mmol) was slowly added at 0 ° C and the mixture was stirred further for 60 min. Et ₂ O (25 mL) was added dropwise, the cooling bath was removed and the mixture was warmed to room temperature. H ₂ O was added and the mixture was extracted 3 times with Et ₂ O. The organic layer was dried over MgSO ₄ merger, filtered and evaporated to give the azide B-1a, which was used without further purification.

Similar to this procedure, other azide B-1 can be prepared from aniline SM-2 .

C. 2. Synthesis of triazole B - 2 C.2.1. Experimental procedure for synthesizing B2-a

Azide B-1a (2.99 g, 12.8 mmol), alkyne SM-5b (3.35 g, 16.3 mmol) and KF (1.33 g, 22.8 mmol) were dissolved in MeOH (60 mL). Sodium ascorbate (7.49 mL, 1 NH ₂ O solution, 7.49 mmol) and CuSO ₄ (0.64 mL, 1 NH ₂ O solution, 0.64 mmol) were added and the mixture was stirred at 45 ° C overnight. The solvent was evaporated, the residue was dissolved in H ₂ O and extracted 2 times with EtOAc. The organic layer was dried over MgSO ₄ merger, filtered and evaporated. The residue was recrystallized from isopropanol to give the triazole B-2a (HPLC-MS: t _retention = 1.25 min; MS (M+H) ⁺ = 367 / 369).

Similar to this procedure, other triazole B-2 can be prepared using various azide B-1 and alkyne SM-5 .

C. 3. Synthesis of aniline B - 6 C.3.1. Experimental procedure for synthesizing B6-a

step 1

Triazole B-2a (1.70 g, 3.70 mmol), benzophenone-imine (794 mg, 4.25 mmol), Pd ₂ (dba) ₃ (197 mg, 0.22 mmol) in an inert atmosphere (N ₂ ) The racemic BINAP (160 mg, 0.25 mmol) and Cs ₂ CO ₃ (4.83 g, 14.8 mmol) were suspended in toluene (40 mL) and stirred at 100 ° C overnight. After cooling to room temperature, the mixture was filtered, taken up on silica gel and purified by EtOAc EtOAc (EtOAc) The fractions of the product containing IM-5a were evaporated, dissolved in MeCN/H ₂ O and lyophilized.

Step 2

IM-5a (1.37 g, 1.76 mmol) was dissolved in THF (10 mL), and concentrated hydrochloric acid (3 mL) was added and the mixture was stirred at 40 ° C for 2 hours, thus forming a precipitate which was collected by filtration. The solid was recrystallized from MeCN to give the aniline B-6a (HPLC-MS: t _retention = 0.99 min; MS (M + H) + = 304), which was used without further purification.

Similar to this procedure, other aniline B-6 was prepared using triazole B-2 and the Buchrich-Hartwig conditions described above.

C. 4. Synthesis of the final compound (I) C.4.1. Experimental procedure for synthesis example I-38

Aniline B-6a (56.6 mg, 0.19 mmol) was suspended in DCM (3 mL), pyridine (60 μL), followed by adding SM-6c (33 μL, 0.24 mmol) and the mixture was stirred overnight at 40 ℃. Aqueous HCl (2 N) was added and the mixture was filtered and evaporated. The residue was dissolved in MeCN/H ₂ O and purified by EtOAc. The fractions of the product containing lyophilized I-38 (HPLC-MS: t _retention = 0.94 min; MS (M+H) ⁺ = 480).

C.4.2. Experimental procedure for synthesis example I-39

Aniline B-6b (153 mg, 0.48 mmol) was suspended in DCM (3 mL), was added sequentially pyridine (60 μL) and SM-6a (180 μL, 1.58 mmol) and the mixture was stirred overnight at 40 ℃. The reaction mixture was concentrated in vacuo,qqqq elut elut elut I-39 evaporation of the product-containing fractions were dissolved (HPLC-MS: t _retention = 0.90 min; MS (M + H) + = 426), was dissolved in MeCN / H ₂ O and freeze-dried in.

Similar to the procedures C.4.1. and C.4.2., other compounds (I) can be prepared using different aniline SM-2 , alkyne SM-5 and sulfonium chloride SM-6 .

The following examples describe the biological activities of the compounds of the invention, but the invention is not limited to such examples.

The compounds of formula (I) are characterized by their many possible applications in the therapeutic field. Particular mention should be made of their use, which involves, for example, the inhibition of specific signal enzymes, especially the proliferation of cultured human tumor cells and the proliferation of other cells, such as endothelial cells.

Kinase Test B - Raf (V600E)

In the dilution series, 10 μL of test substance solution per well was placed in a multi-well plate. The dilution series is selected to generally cover a concentration range of 2 μM to 0.119 nM or 0.017 nM. If necessary, the initial concentration of 2 μM was changed to 50 μM, 10 μM, 0.4 μM or 0.2857 μM and further dilution was carried out accordingly. The final concentration of DMSO was 5%. Pipette 10 μL of B-Raf(V600E)-kinase solution per well (20 mM Tris-HCl (pH 7.5), 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% C3) Alcohol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol contained 0.5 ng of B-Raf (V600E)-kinase (eg, from Upstate), and the mixture was incubated for 1 hour at room temperature under shaking. By adding 20 μL of ATP solution per well [final concentration: 250 μM ATP, 30 mM Tris-HCl (pH 7.5), 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA, phosphatase mix Solution (Sigma, #P2850, manufacturer recommended dilution) and 10 μL MEK1 solution per well [containing 50 ng biotinylated MEK1 (prepared from purified MEK1 according to standard procedures, eg with EZ-Link Sulpho-NHS-LC -Biotin reagent (Pierce, # 21335))] The kinase reaction was initiated and carried out at room temperature for 60 minutes under constant shaking. The reaction was stopped by adding 12 μL of 100 mM EDTA solution per well and incubation was continued for another 5 minutes. Transfer 55 μL of the reaction solution per well to a streptavidin-coated plate (eg Streptawell HighBond, Roche, #11989685001) and gently shake at room temperature for 1 hour to allow biotin-labeled MEK1 to bind to the culture. plate. After removing the liquid, the plate was washed five times with 200 μL of 1×PBS per well and 100 μL of primary antibody plus ruthenium-labeled secondary antibody per well [anti-phosphate MEK (Ser217/221), Cell Signaling, # 9121; and Eu) a solution of -N1 labeled goat anti-rabbit antibody, Perkin Elmer, #AD0105], diluted with a 1:2000 dilution of the antibody with Delfia assay buffer (Perkin Elmer, #1244-111) and diluted to a secondary antibody to 0.4-0.5 μg/ mL. After shaking for 1 hour at room temperature, the solution was decanted and washed five times with 200 μL of Delfia Wash Buffer (Perkin Elmer, #4010-0010/# 1244-114) per well. After adding 200 μL of enhancement solution per well (Perkin Elmer, # 4001-0010/# 1244-105), the mixture was shaken at room temperature for 10 minutes, and then the procedure "Delfia Time Difference Fluorescence (铕)" was used with Wallac Victor. Measure. Using software programs (GraphPadPrizm) whereby isodose - ₅₀ activity curves obtained value IC.

Measurement of cultured human melanoma cells (SK - MEL - 28, B - RAF) ^V600E Inhibition of proliferation of mutants)

For the proliferation of cultured human tumor cells, supplemented with 10% fetal bovine serum, 2% sodium bicarbonate, 1 mM sodium pyruvate, 1% non-essential amino acid (eg from Cambrex, # BE13-114E) and Cells of melanoma cell line SK-MEL-28 were cultured in 2 mM branic acid MEM medium [from American Type Culture Collection (ATCC)]. SK-MEL-28 cells were plated in a 96-well flat-bottom tray at a density of 2500 cells per well in supplemented MEM medium (see above) and in an incubator (at 37 ° C and 5% CO ₂ ) Cultivate overnight. The active substance is added to the cells at different concentrations to cover a concentration range of 50 μM to 3.2 nM. If necessary, the initial concentration of 50 μM was changed to 10 μM or 2 μM, and thus further dilution (up to 0.6 nM or 0.12 nM) was carried out. After an additional 72 hour incubation period, 20 μL of AlamarBlue reagent (Serotec Ltd., # BUF012B) was added to each well and the cells were incubated for a further 3 hours to 6 hours. The discoloration of the AlamarBlue reagent was measured using a fluorescence spectrophotometer (e.g., Gemini, Molecular Devices). The EC ₅₀ value was calculated using a software program (GraphPadPrizm).

Examples of the above EC determined using the assay of the ₅₀ values of the compounds shown in Table 9.

Measurement of cultured human melanoma cells (A375, B - RAF) ^V600E Inhibition of proliferation of mutants)

For the proliferation of cultured human tumor cells, cells of melanoma cell line A375 [from the American Type Culture Collection (ATCC)] were cultured in DMEM medium supplemented with 10% fetal bovine serum and 2% sodium bicarbonate. Test substances were tested on A375 cells according to the procedure described for SK-MEL-28 cells (see above), but were seeded at 5000 cells per well.

A375 cells in most assays examples of compounds I-1 to I-76 all show good to excellent activity of, i.e., EC ₅₀ value of less than 1000 nM, typically less than 500 nM.

The active substance is characterized in that it has a significantly lower antiproliferative activity against a cell line free of B-RAF mutations. Thus, for example, examples of compounds I-1 to I-76 to B-Raf V600E mutant None of melanoma cells (e.g. of A375) than the EC ₅₀ value is generally mutant B-RAF melanoma cells (e.g. of A375) At least 10 times higher.

Phosphate -ERK reduce the EC ₅₀ value and a B-RAF mutated cell lines the anti-proliferative activity of EC ₅₀ values correlate well with the cell selectivity of the active material.

Measurement of cultured human melanoma cells (SK - MEL - 28, B - RAF ^V600E Burst Variant) reduction of phosphoric acid - ERK signal

To measure the decrease in phospho-ERK signal in cultured human tumor cells, supplemented with 10% fetal bovine serum, 2% sodium bicarbonate, 1 mM sodium pyruvate, 1% non-essential amino acid (eg obtained from Cambrex, # BE13-114E) and cells of melanoma cell line SK-MEL-28 were cultured in MEM medium of 2 mM branic acid [from the American Type Culture Collection (ATCC)]. SK-MEL-28 cells were plated in 96-well flat-bottomed plates at a density of 7500 cells per well in supplemented MEM medium (see above) and incubated in an incubator (at 37 ° C and 5% CO ₂ ) Overnight. The active substance is added to the cells at different concentrations to cover a concentration range of 10 μM to 2.4 nM. If necessary, the initial concentration of 10 μM was changed to 50 μM or 2.5 μM, and further dilution was performed accordingly (up to 12.2 nM or 0.6 nM). After an additional 2 hour incubation period, cells were fixed with 4% formaldehyde and infiltrated with PBS containing 0.1% Triton X-100. Non-specific antibody binding was reduced by incubation with a 5% skim milk powder solution dissolved in TBS-T. Phosphorylated ERK was detected by murine monoclonal antibody anti-diphosphorylation of ERK1/2 antibody (from Sigma, #M8159). After the washing step with PBS containing 0.1% Tween 20, the bound primary antibody was detected by a second antibody (peroxidase-coupled multiple rabbit anti-mouse IgG, from DAKO #P0161). After the other washing steps, the substrate (TMB peroxidase receptor solution prepared by Bender MedSystems #BMS406) was added. The color reaction was stopped with 1 M phosphoric acid after a few minutes. Staining was measured at 450 nm using a Spectra Max Plus reader manufactured by Molecular Devices. The EC ₅₀ value was calculated using a software program (GraphPadPrizm).

Measured using the above assay the compounds of Examples phosphate -ERK reduce the EC ₅₀ values generally less than 500 nM.

The substance of the invention is a B-RAF-kinase inhibitor. The inhibition of proliferation achieved by means of the compounds of the invention can be effected, inter alia, by preventing DNA from entering the stage of DNA synthesis, as indicated by DNA staining, followed by FACS or Cellomics array scanning analysis. The treated cells are arrested in the G1 phase of the cell cycle.

Therefore, the compounds of the invention were also tested on other tumor cells. For example, such compounds are effective against colon cancer cell lines (eg, Colo205, HT29) and are useful in colon cancer and other indications. This indicates that the compounds of the invention are useful in the treatment of different types of tumors.

The biological properties of the compounds of the general formula (I) , their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and salts of all the above forms based on the present invention, which are suitable for use in Therapeutic features are diseases of excessive or abnormal cell proliferation.

Such diseases include, for example, viral infections (such as HIV and Kaposi's sarcoma); inflammatory diseases and autoimmune diseases (such as colitis, arthritis, Alzheimer's disease, silk). Spherical nephritis and wound healing); bacterial, fungal and/or parasitic infections; leukemias, lymphomas and solid tumors (eg cancers and sarcomas), skin diseases (eg psoriasis); hyperplasia-based diseases characterized by cells (eg The number of fibroblasts, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (eg, endometrial hyperplasia) is increased; bone diseases and cardiovascular diseases (eg, restenosis and hypertrophy). It is also suitable for protecting proliferating cells (such as hair, intestines, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.

For example, but not limited to, the following cancers can be treated with the compounds of the invention: brain tumors, such as acoustic neuroma, astrocytoma (such as cystic astrocytomas, fibroblast astrocytoma, Protoplasmic astrocytoma, obese astrocytoma, degenerative astrocytoma, and glioblastoma, brain lymphoma, brain metastasis, pituitary tumors (such as prolactinoma), production HGH (human growth hormone) tumors and ACTH-producing tumors (adrenocorticotropic hormone), craniopharyngioma, medulloblastoma, meningioma and oligodendroglioma; neuro-tumor (tumor), such as vegetal Tumors of the nervous system, such as sympathetic neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and carotid tumors, tumors on the peripheral nervous system (such as amputation neuroma, neurofibromatosis, neuronioma (neurilemmoma, Schwannoma) and malignant Schwannoma and central nervous system tumors, such as the brain and Bone marrow neoplasms; intestinal cancers, such as rectal cancer, colon cancer, colorectal cancer, anal cancer, colorectal cancer, small intestine and duodenum; orbital tumors, such as basaloma or basal cell carcinoma; pancreatic cancer or pancreas Carcinoma; bladder cancer or bladder cancer; lung cancer (bronchial lung cancer), such as small cell bronchial carcinoma (oat cell carcinoma) and non-small cell bronchial carcinoma (NSCLC) (such as squamous cell carcinoma, adenocarcinoma, and large cell bronchi) Lung cancer); breast cancer, such as breast cancer, such as invasive breast ductal carcinoma, colloidal carcinoma, invasive lobular carcinoma, tubular cancer, adenoid cystic carcinoma, and papillary carcinoma; non-Hodgkin's lymphomas , NHL), such as Burkitt's lymphoma, low malignancy Non-Hodgkin's lymphoma (NHL) and mycosis fungoides; uterine or endometrial or endometrial cancer; CUP syndrome (unidentified primary cancer); ovarian or ovarian cancer, such as mucinous carcinoma, intrauterine Membrane or serous carcinoma; gallbladder carcinoma; cholangiocarcinoma, such as Klatskin tumour; testicular cancer, such as seminoma and non-seminoma; lymphoma (lymphosarcoma), such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (NHL), such as chronic lymphocytic leukemia, leukaemic reticuloendotheliosis, immune cell tumor, plasmacytoma (multiple bone marrow) Tumor), immunoblastoma, Burkitt's lymphoma, T-zone mycosis, large cell degenerative lymphoblastoma, and lymphoblastoma; laryngeal cancer, such as vocal cord tumor, glottis, glottis, and glottic Laryngeal neoplasms; bone cancers such as osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroids, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell Tumor, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulum sarcoma, plasmacytoma, fibrous dysplasia, adolescent bone cyst and aneurysmal bone cyst; head and neck tumors, such as the lips, Tongue, mouth, mouth, gums, palate, salivary gland, throat, nasal cavity, paranasal sinus, throat and middle ear; liver cancer, such as liver cell carcinoma or hepatocellular carcinoma (HCC); leukemia, such as acute leukemia, Such as acute lymphocyte/lymphocytic leukemia (ALL), acute myeloid leukemia (AML); chronic leukemia, such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML); gastric or gastric cancer, such as papillary, tubular and Mucinous adenocarcinoma, ring cell carcinoma, adenosquamous carcinoma, small cell carcinoma and undifferentiated carcinoma; melanin Tumors, such as superficial diffuse, nodular, malignant small sputum and acral freckle melanoma; kidney cancer, such as renal cell carcinoma or adrenal adenoma or Grawitz's tumour; esophageal cancer Or esophageal cancer; penile cancer; prostate cancer; laryngeal or pharyngeal cancer, such as nasopharyngeal carcinoma, oropharyngeal cancer and hypopharyngeal carcinoma; retinoblastoma; vaginal or vaginal cancer; squamous cell carcinoma, adenocarcinoma, Carcinoma in situ, malignant melanoma and sarcoma; thyroid cancer, such as papillary, follicular and medullary thyroid cancer, and degenerative carcinoma; skin with spinalioma, epidermoid carcinoma ) and squamous cell carcinoma; thymoma, urethral cancer and vulvar cancer.

Novel compounds can be used for the prophylactic, short-term or long-term treatment of these diseases, optionally in combination with radiation therapy or other "currently advanced technology" compounds such as cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies. .

The compounds of the general formula (I) can be used either singly or in combination with other active substances of the invention, optionally in combination with other pharmacologically active substances.

Chemotherapeutic agents that can be administered in combination with the compounds of the invention include, but are not limited to, hormones, hormone analogs, and anti-hormones (e.g., tamoxifen, toremifene, raloxifene) ), fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide , cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoromethanone (fluoxymesterone), medroxyprogesterone, octreotide, aromatase inhibitors (eg anastrozole, letrozole, liarozole, fluconazole) Vorozole), exemestane, atamestane, LHRH agonists and antagonists (eg, goserelin acetate, luprolide), growth factors Inhibitors (growth factors such as "platelet-derived growth factor (PDGF)", "fibroblast growth factor (FGF)", "vascular endothelial growth factor (VEGF)", "epidermal growth factor (EGF)", "insulin-like growth" Factor (IGF), "human epidermal growth factor (HER, eg HER2, HER3, HER4)" and "hepatocyte growth factor (HGF)", inhibitors such as "growth factor" antibody, "growth factor receptor" antibody And tyrosine kinase inhibitors (such as cetuximab, gefitinib, imatinib, lapatinib, and trastuzumab) Antimetabolite (eg antifolate, such as methotrexate (methotrex) Ate), raltitrexed, pyrimidine analogs (such as 5-fluorouracil, capecitabin and gemcitabine), purines and adenosine analogues (such as mercaptopurine, sulphur birds) Thioguanine, cladribine and pentostatin, cytarabine, fludarabine; antitumor antibiotics (eg anthracyclin) Such as cranberry (doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin (bleomycin), dactinomycin, plicamycin, streptozocin, platinum derivatives (eg cisplatin, oxaliplatin, carboplatin) (carboplatin)); alkylating agents (eg estracumin, meclorethamine, melphalan, chlorambucil, busulphan, da Dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosourea (such as carmustin and lomustin, Thietepa; anti-mitotic agents (eg, vinca alkaloids such as vinblastine, vindesin, vinorelbin, and vincristine; and taxanes) (taxane), such as paclitaxel, docetaxel; tubulin inhibitors; PARP inhibitors, topoisomerase inhibitors (eg epipodophyllotoxin (such as etoposide) Etoposide) and etopophos, teniposide, ampoules Azacrin, topotecan, irinotecan, mitoxantron, serine/threonine kinase inhibitors (eg PDK 1 inhibitor, B-Raf Inhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors, tyrosine Kinase inhibitors (eg PTK2/FAK inhibitors), protein interaction inhibitors (eg IAP, Mcl-1, MDM2/MDMX), MEK inhibitors, ERK inhibitors, IGF-1R inhibition Agents, ErbB receptor inhibitors, rapamycin analogues (eg everolimus, temsirolimus, ridaforolimus, sirolimus) and various Chemotherapeutic agents, such as amifostine, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin , rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porphyrin ( Porfimer).

Other possible combinations are 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-alethine, 131-I-TM -601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin, ali Alitretinoin, alovectin-7, altretamine, avocidib, amonafide, anthrapyrazole, AG- 2037, AP-5280, azaziquone, apomine, aranose, arglabin, arzoxifene, atamestane ), atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY- 142886/AZD-6244 (selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244 , ARQ-736, ARQ 680, AS-703026 (primasertib), Ava Avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR- 3464, BBR-3576, bevacizumab, BEZ-235, biricodar dicitrate, BCX-1777, BKM-120, bleocin sulfate, BLP-25 , BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW 2992 (afatinib, tomotok (tomtovok) )), BIBF 1120 (vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI 853520, BIIB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib, brostallicin, busulphan, BYL -719, CA-4 prodrug, CA-4, CapCell, calcitriol, carnitinib, canfosfamide, capecitabine, carboxyl phthalate Phenylphthalatoplatin , CCI-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftrixone, senecis ( Celecoxib), celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-II , CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-Thera, CMT-3 from C. acuminata 52 (CMT-3 cryptophycin 52), CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, cyanomorpholinic cranberry, A Cytosine, D 24851, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, go Epothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, dolphin toxin 10 (dol Astatin 10), dorididazole, DS-7423, E7010, E-6201, edatrexat, edotreotide, efaproxiral, efloxacin Acid (eflornithine), EGFR inhibitor, EKB-569, EKB-509, enzastaurin, elsamitrucin, epothilone B, epratuzumab, ER- 86526, erlotinib, ET-18-OCH3, ethynyl cytidine, ethynyl estradiol, exatecan, ezetimibe mesylate, exemestane , exisulind, fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI, formestane, formo Fotemustine, galarubicin, gallium maltolate, gefitinib, gemtuzumab, gimatecan, glucosamine Glufosfamide), GCS-IOO, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A , GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine, histamine, homoharringtonine, Hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate , idenestrol, IDN-5109, IGF-1R inhibitor, IMC-1C11, IMC-A12 (cixutumumab), immunol, indisulam ), interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117, INK-128, INSM-18, ionafarnib, Ipilimumab, iproplatin, irofulven, isohomohohodhond-B, isoflavone ), isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated estrogen, kahalid F, ketoconazole, KW - 2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lysine (lexidronam), LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, letotecan (lurtotecan) , LY-S6AKT1, LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitor, MEK-162, methyltestosteron, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin (mitomycin), mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexafin gadolinium, MS-2 09, MS-275, MX6, neridronate, neratinib, Nexavar, neovastat, nilotinib, nimesul Nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, oblimersen, Omeprazole, oncophage, oncoVEX ^GM-CSF , ormiplatin, ortataxel, OX44 antibody, OSI-027, OSI-906 Lintintinib, 4-1BB antibody, oxantrazole, estrogen, panitumumab, patupilone, pegfilgrastim , PCK-3145, PEGylated filgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin stabilized paclitaxel, PEP-005, PF-05197281, PF- 05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, piperazine New (perif Osine), perillylalcohol, pertuzumab, PI3K inhibitor, PI3K/mTOR inhibitor, PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib) ), PLX-3603/RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, p-pentyloxymethyl butyrate, pixantrone, phenytoin O (phenoxodiol O), PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, splashed nylon (prednisolone), quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436 , rebeccamycin analogues, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, Rhizoxin, rhu-MAb, rinfabate, risedronate, rituximab, robatumumab, rofecoxib Rofecoxib), RO -31-7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S- 9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101, semustine (semustin), seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, snail Spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103, Tektronix ( Tacedinaline), talaporfin, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin, he Tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, Tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therrabicin, thymalfasin , thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, toltudex, tormo Torememo, trobectedin, TransMID-107, transretinic acid, trastuzumab, tremelimumab, tretinoin , triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258, lapertib/tyverb, yupidine Urocidin, valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1, WX-554, victorium (vectibix) ), Xeloda, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598 ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZDI839, ZSTK-474, zoledronat and zosuquidar.

Suitable formulations include, for example, lozenges, capsules, suppositories, solutions (especially injectable (subcutaneous, intravenous, intramuscular) and infusion solutions), elixirs, emulsions or dispersible powders. The amount of the pharmaceutically active compound should be in the range of from 0.1% by weight to 90% by weight, preferably from 0.5% by weight to 50% by weight of the total composition, i.e., in an amount sufficient to achieve the dosage range shown below. The indicated doses may be provided several times a day if necessary.

Suitable lozenges can be obtained, for example, by mixing the active substances with known excipients such as inert diluents such as calcium carbonate, calcium phosphate or lactose; disintegrating agents such as corn starch Or alginic acid; a binder such as starch or gelatin; a lubricant such as magnesium stearate or talc; and/or an agent for delayed release, such as carboxymethylcellulose, cellulose acetate phthalate or polyacetic acid Vinyl ester. The tablets may also comprise several layers.

Therefore, the coated tablet can be coated with a core similar to a tablet by using a substance commonly used for tableting (for example, collidone or shellac, gum arabic, talc, titanium dioxide or sugar). To prepare. To achieve delayed release or to prevent incompatibility, the core can also be composed of many layers. Similarly, the drag coating can be composed of a number of layers to achieve delayed release, possibly using the excipients described above for tablets.

A syrup or elixir containing the active substance of the present invention or a combination thereof may additionally contain a sweetener such as saccharin, cyclohexylamine sulfonate, glycerol or sugar, and a flavor enhancer such as a flavoring agent such as vanilla extract or orange. Extract. It may also contain a suspension adjuvant or a thickening agent such as sodium carboxymethylcellulose, a wetting agent such as a condensation product of a fatty alcohol with ethylene oxide or a preservative such as a paraben.

Injection and infusion solutions are prepared in a conventional manner, such as the addition of an isotonic agent, a preservative (such as a paraben) or a stabilizer (such as an alkali metal salt of ethylenediaminetetraacetic acid), optionally using an emulsifier and / or dispersant, while using water as a diluent, for example, the organic solvent can be used as a solvating agent or a dissolution aid, and transferred to an injection vial or an ampoule or infusion bottle.

Capsules containing one or more active substances or a combination of active substances can be prepared, for example, by mixing the active substance with an inert carrier such as lactose or sorbitol and packaging it in a gelatin capsule.

Suitable suppositories can be prepared, for example, by mixing with a carrier, such as a neutral fat or polyethylene glycol or a derivative thereof, provided for this purpose.

Excipients which may be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fraction); vegetable oils (e.g., peanut oil or sesame) Oil); monofunctional or polyfunctional alcohols (eg ethanol or glycerol); carriers such as natural mineral powders (eg kaolin, clay, talc, chalk); synthetic mineral powders (eg highly dispersed tannins and niobates) ); saccharides (such as sucrose, lactose and glucose); emulsifiers (such as lignin, sulphite waste, methyl cellulose, starch and polyvinylpyrrolidone); and lubricants (such as magnesium stearate, talc, Stearic acid and sodium lauryl sulfate).

The preparation is administered by a conventional method, preferably by an oral or transdermal route, preferably by an oral route. For oral administration, the tablet may contain, in addition to the above carrier, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, and various kinds such as starch (preferably potato starch), gelatin and the like. additive. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used in the ingot making process at the same time. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or colorants other than the above-mentioned excipients.

For parenteral use, solutions of the active substance with a suitable liquid carrier can be employed.

The dose for intravenous use is from 1 mg to 1000 mg per hour, preferably between 5 mg and 500 mg per hour.

However, depending on the body weight, the route of administration, the individual's response to the drug, the nature of the formulation, and the time or time interval at which the drug is administered, it may sometimes be necessary to deviate from the indicated amount. Therefore, in some cases, it may be sufficient to use less than the minimum dose given above, while in other cases, the upper limit may have to be exceeded. When administered in large quantities, it should be divided into smaller doses throughout the day.

The following formulation examples illustrate the invention without limiting its scope:

Examples of pharmaceutical formulations

The finely ground active substance, lactose and some corn starch are mixed together. The mixture was screened, followed by wetting with a solution of polyvinylpyrrolidone in water, kneading, wet granulation and drying. The granules, remaining corn starch and magnesium stearate are screened and mixed together. The mixture is compressed to produce a lozenge of suitable shape and size.

The finely ground actives, some corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together, the mixture is screened and processed with the remaining corn starch and water to form granules which are dried and screened. Sodium carboxymethyl starch and magnesium stearate are added and mixed together, and the mixture is compressed to form tablets of appropriate size.

The active substance is dissolved in water to its own pH or, as the case may be, pH 5.5 to 6.5, and sodium chloride is added to make it isotonic. The resulting solution was filtered to be pyrogen free, and the filtrate was transferred to an ampoule under sterile conditions, followed by sterilization and sealing by melt. Ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims (40)

a compound of the formula (I) , Wherein R ² is a group optionally substituted by one or more of the same or different R ^b1 and/or R ^c1 selected from C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _6-10 aryl, 5 to 10 membered heteroaryl and 3 to 10 membered heterocyclic ring Or R ² is -NR ^c1 R ^c1 ; each R ^{b1 is} independently selected from -OR ^c1 , -NR ^c1 R ^c1 , halogen, -CN, -C(O)R ^c1 , -C(O)OR ^c1 , -C(O)NR ^c1 R ^c1 , -S(O) ₂ R ^c1 , -S(O) ₂ NR ^c1 R ^c1 , -NHC(O)R ^c1 and -N(C _1-4 alkyl)C( O) R ^c1 , and a divalent substituent=O, wherein the divalent substituent=O can only be a substituent in a non-aromatic ring system; each R ^c1 independently of one another represents hydrogen or a group selected from the group consisting of C: _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _6-10 aryl a 5 to 10 membered heteroaryl group and a 3 to 10 membered heterocyclic group; - R ³ is selected from the group consisting of hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, -CN, -NH(C _1-4 alkyl) and -N(C _1-4 alkyl) ₂ ;--ring A is 5 to 10 members heteroaryl; - m represents a number 0, 1 or 2; each R ⁴ independently of one another Shows optionally substituted with one or more identical or different R ^a2 and / or substituted radicals of R ^b2, which is selected from C _1-6 alkyl, C _C2-6 alkenyl group, C _C2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _6-10 aryl, 5 to 10 membered heteroaryl and 3 to 11 membered heterocyclic group, or independently selected From -OR ^a3 , -NR ^a3 R ^a3 , -N(OR ^a3 )R ^a3 , halogen, -CN, -C(O)R ^a3 , -C(O)OR ^a3 , -C(O)NR ^a3 R ^a3 , -C(NH)NR ^a3 R ^a3 , -S(O) ₂ R ^a3 , -S(O) ₂ NR ^a3 R ^a3 , -NHC(O)R ^a3 and -N(C _1-4 alkyl)C (O) R ^a3 Each R ^a2 independently of one another represents a group optionally substituted by one or more of the same or different R ^{b 2} and/or R ^{c 2} , which is selected from C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^{b 2 is} independently selected from - OR ^c2 , -NR ^c2 R ^c2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC(O)R ^c2 and -NHC (O)OR ^c2 ; each R ^c2 independently of one another represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl a C _4-6 cycloalkenyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group Substituting one or more substituents of the same or different selected from the group consisting of halogen, C _1-6 alkyl and -C(O)-C _1-6 alkyl; each R ^a3 independently represents hydrogen or a group optionally substituted with one or more of the same or different R ^{b 3} and/or R ^c3 selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^{b3 is} independently selected from -OR ^c3 , -NR ^c3 R ^c3 , halogen, - C(O)R ^c3 , -C(O)OR ^c3 , -C(O)NR ^c3 R ^c3 , -CN, -NHC(O)R ^c3 and -NHC(O)OR ^c3 ; each R ^{c3 is} independently of each other Represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _{1- 6} alkyl-OC _1-6 alkyl, (C _1-4 alkyl)HN-C _1-6 alkyl, (C _1-4 alkyl) ₂ NC _1-6 alkyl, C _1-6 halo a 4- to 16-membered heterocycloalkyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group in the above group is optionally substituted by one or more C _1-6 alkyl groups which may be the same or different; X represents chlorine or fluorine; - wherein such compounds (I) may also optionally their tautomers, racemates, enantiomers, non- Enantiomeric forms thereof or mixtures thereof is present in all of those respective salt forms of the above forms. The compound of claim 1, wherein R ² is selected from the group consisting of C _1-6 alkyl, C _1-4 alkoxy-C _1-4 alkyl, 5 to 6 membered heteroaryl, C _3-6 cycloalkyl , C _4-7 cycloalkylalkyl and phenyl, substituted by one or more of the same or different halogens. A compound according to claim 2, wherein R ² represents C _1-6 alkyl or phenyl, substituted by one or more of the same or different halogens. The compound of claim 3, wherein R ² represents a C _1-6 alkyl group. The compound of claim 4, wherein R ² is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. The compound of claim 5, wherein R ² is selected from the group consisting of ethyl, n-propyl, isopropyl and isobutyl. The compound of claim 6, wherein R ² is n-propyl. The compound of claim 2, wherein R ² is 5 to 6 membered heteroaryl. A compound of claim 8 wherein R ² is furyl or pyridyl. The compound of claim 9, wherein R ² is a furyl group. The compound of claim 10, wherein R ² is . The compound of claim 2, wherein R ² is difluorophenyl. The compound of any one of claims 1 to 12, wherein R ³ is halogen. The compound of claim 13, wherein R ³ is fluoro. The compound of any one of claims 1 to 12, wherein ring A is a nitrogen-containing 5 to 10 membered heteroaryl group. The compound of claim 15, wherein ring A is a nitrogen-containing 5 to 6 membered heteroaryl group. The compound of claim 16, wherein the ring A is selected from the group consisting of pyridyl, pyrimidinyl and pyrazolyl. The compound of claim 17, wherein ring A is pyridyl. The requested item 1 to a compound of 12, wherein m represents 1; ^{R. 4} is a 3-11 heterocyclyl group, optionally substituted with one or more identical or different R ^a2 and / or substituted with R ^b2 each R ^A2 independently of each other represents a group optionally substituted with one or more of the same or different R ^{b 2} and/or R ^c2 selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^{b2 is} independently selected from -OR ^c2 , -NR ^c2 R ^C2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC(O)R ^c2 and -MHC(O)OR ^c2 , and Each R ^c2 independently of one another represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-6 ring An alkenyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more substituents which may be the same or different selected from the group consisting of halogen, C _1-6 alkyl and -C(O)- C _1-6 alkyl. The compound of the requested item 19, wherein m represents 1; R ⁴ is 4-7 nitrogen-containing heterocyclic group, optionally substituted with one or more identical or different substituents R ^a2 and / or R ^b2 independently of one another each R ^a2 a group which is optionally substituted with one or more of the same or different R ^{b 2} and/or R ^c2 selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{a 1-6} haloalkyl group, a C _3-6 cycloalkyl group, a C _4-6 cycloalkenyl group, and a 3 to 10 membered heterocyclic group; each R ^{b2 is} independently selected from the group consisting of -OR ^c2 , -NR ^c2 R ^c2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC(O)R ^c2 and -NHC(O)OR ^c2 , and each R ^c2 are each other Independently represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 To a 10-membered heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more substituents of the same or different selected from the group consisting of halogen, C _1-6 alkyl and -C(O)-C _1-6 alkyl. The compound of claim 20, wherein m represents 1; R ⁴ is selected from the group consisting of piperazinyl, piperidinyl and morpholinyl, all of which are optionally substituted by one or more of the same or different R ^a2 and/or R ^b2 Each R ^a2 independently of one another represents a group optionally substituted with one or more of the same or different R ^{b 2} and/or R ^c2 selected from C _1-6 alkyl, C _2-6 alkenyl, C _{2 . -6} alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl and 3 to 10 membered heterocyclic; each R ^{b2 is} independently selected from -OR ^c2 , -NR ^C2 R ^c2 , halogen, -C(O)R ^c2 , -C(O)OR ^c2 , -C(O)NR ^c2 R ^c2 , -CN, -NHC(O)R ^c2 and -NHC(O)OR ^c2 And each R ^c2 independently of each other represents hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _{4- a 6} cycloalkenyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of halogen, C _1-6 alkyl and -C(O). )-C _1-6 alkyl group. The compound of claim 21, wherein each R ^a2 independently of one another represents a group optionally substituted with one or more of the same or different R ^{b 2} and/or R ^c2 selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl and 3 to 10 membered heterocyclic; each R ^{b2 is} independently selected from -OR ^c2 , -NR ^C2 R ^c2 , halogen, —C(O)NR ^{c 2} R ^c2 and —CN, and each R ^{c 2} independently of each other represent hydrogen or a group selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl And a 3 to 10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more substituents which may be the same or different selected from the group consisting of halogen, C _1-6 alkyl and -C(O)-C _{1 -6} alkyl. The compound of any one of claims 1 to 12, wherein m represents 1; R ⁴ is selected from the group consisting of -OR ^a3 and -NR ^a3 R ^a3 ; each R ^a3 independently represents hydrogen or, as the case may be, one or more Or a group substituted by R ^b3 and/or R ^c3 , which is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _{3 a -6} cycloalkyl group, a C _4-6 cycloalkenyl group and a 3 to 10 membered heterocyclic group; each R ^{b3 is} independently selected from -OR ^c3 , -NR ^c3 R ^c3 , halogen, -C(O)R ^c3 ,- C(O)OR ^c3 , -C(O)NR ^c3 R ^c3 , -CN, -NHC(O)R ^c3 and -NHC(O)OR ^c3 ; each R ^c3 independently of each other represents hydrogen or a group selected from Group: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl, C _1-6 alkyl-OC _1-6 Alkyl, (C _1-4 alkyl)HN-C _1-6 alkyl, (C _1-4 alkyl) ₂ NC _1-6 alkyl, C _1-6 haloalkyl, 4 to 16 membered heterocyclic ring An alkyl group and a 3 to 10 membered heterocyclic group, wherein the heterocyclic group in the above group is optionally substituted by one or more of the same or different C _1-6 alkyl groups. The compound of any one of claims 1 to 12, wherein m represents 1, and R ⁴ is imidazolyl, optionally substituted by one, two or three identical or different C _1-4 alkyl groups. The compound of any one of claims 1 to 12, wherein m represents 0. The compound of any one of claims 1 to 12, wherein m represents 1; R ⁴ and ring A together Wherein R ⁵ is C _1-6 alkyl. The compound of claim 26, wherein m represents 1, and R ⁴ and ring A together The compound of any one of claims 1 to 12, wherein m represents 1, and R ⁴ and ring A together Wherein R ⁶ is selected from the group consisting of fluorine, chlorine and bromine. The compound of any one of claims 1 to 12, wherein m represents 1, and R ⁴ and ring A together Wherein R ⁷ is selected from the group consisting of C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-12 cycloalkylalkyl, 3 to 6 membered heterocyclic, -C ( O) C _1-6 alkyl and C _1-6 alkoxy-C _1-6 alkyl. The compound of claim 29, wherein m represents 1, and R ⁴ and ring A together Wherein R ⁷ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, C _4-12 cycloalkylalkyl, -C(O)C _1-6 alkyl, and C _1-6 alkoxy Base-C _1-6 alkyl. The compound of any one of claims 1 to 12, wherein X represents chlorine. The compound of any one of claims 1 to 12, wherein X represents fluorine. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: A compound of the formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound of the formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancer, infection, inflammation and autoimmune diseases. A compound of the formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancer. A compound of the formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of colon cancer, melanoma, gallbladder cancer and thyroid cancer. A use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 33 for the manufacture of a medicament for the treatment and/or prevention of cancer. A pharmaceutical preparation comprising one or more compounds of the formula (I) according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, as an active substance, optionally combining conventional excipients and/or carriers . A pharmaceutical preparation comprising a compound of the formula (I) according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof and at least one other cytostatic or cytotoxic activity different from the formula (I) substance.