N-Heterocyclic Carbene Complexes for Transition Metal Catalysis

Abstract

A novel class of highly active Pd(II)-NHC complexes containing aniline as a disposable ligand is described herein. These catalysts are well-defined, stable to air and moisture, and easily purified by chromatographic techniques. Their high activity and versatility in Suzuki-Miyaura cross-coupling reactions via C-N, C-O, and C-Cl cleavage are demonstrated. A facile synthesis of these catalysts is also described. TIFF2023509963000063.tif99150

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 958,583, filed on January 8, 2020, entitled "COMPLEXES OF N - HETEROCYCLIC CARBENES FOR TRANSITION METAL CATALYSIS", the entire content of which is incorporated herein by reference.

[0002] Description of Research Sponsored by the Federal Government This invention was made with government support under Grant Nos. CHE1650766 awarded by the National Science Foundation of the United States and GM133326 awarded by the National Institutes of Health of the United States. The government has certain rights in this invention.

Background Art

[0003] Background Palladium - catalyzed cross - coupling reactions have revolutionized the synthesis of small molecules. This has become one of the most important methods in the construction of diverse chemical substances. In particular, in recent years, well - defined Pd(II) precatalysts have emerged that enable the use of an optimal 1:1 Pd - to - ligand ratio in simple - to - operate protocols. Some of these precatalysts, including Nolan's [Pd(NHC)(allyl)Cl] and [Pd(NHC)(cin)Cl] complexes, Organ's Pd - PEPPSI system, Hazari's [Pd(NHC)(ind)Cl] catalyst, or Buchwald's G1 - G4 paracyclophanes, are currently commercially available, enabling direct application and reaction optimization by end - users.

[0004] NHC (NHC = N - heterocyclic carbene) was originally designed as a complement to phosphine, but has shown significant advantages as a co - ligand in Pd catalysis, including strong σ - donation and steric tuning around the metal center. The stabilization of palladium by amine - type nitrogen is a major feature of the Nolan and Buchwald paracyclic cycles. As an ideal catalyst design criterion, the disposable ligand should be easily removed during the activation step to obtain an active monocoordinated Pd(0) complex, while its recombination stabilizes the active metal species, making it possible to extend the catalyst life.

[0005] Therefore, there is a need in the art for novel complexes that can be used as catalysts in cross - coupling reactions. The present invention addresses this need.

Summary of the Invention

[0006] Brief Summary of the Invention In various aspects, the present disclosure provides a compound of formula I, or a salt or solvate thereof: TIFF0007693229000001.tif53128 wherein, TIFF0007693229000002.tif2128 is a single bond or a double bond; R 1 and R 2 are each independently C 3~10 cycloalkyl, aryl, or heteroaryl, each of which is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C6~10 optionally substituted with at least one group selected from the group consisting of heteroaryl; R 3 and R 4 are each independently hydrogen, optionally substituted C 3~10 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C 1~12 alkyl, or OC 1~12 alkyl, wherein any substitution is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and contain at least one group selected from the group consisting of; or, R 3 and R 4 together with the ring to which they are attached, are used to form C 4~20 cycloalkyl, C 6~20 aryl, or C 6~20 heteroaryl, each of which is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C6~10 Aryl, and C 6~10 optionally substituted with at least one group selected from the group consisting of heteroaryl; R 5 is H or optionally substituted C 1~3 alkyl; M is a transition metal; X is a counteranion; A is aryl or heteroaryl, halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 optionally substituted with at least one group selected from the group consisting of heteroaryl; each R is independently hydrogen or C 1~10 alkyl; m is 1, 2, or 3; n is 1, 2, 3, or 4.

[0007] In various embodiments, provided is a method for preparing a compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof. The method includes contacting, in a solvent, a compound having the following structure: TIFF0007693229000003.tif57128, or a salt, solvate, geometric isomer, or stereoisomer thereof, with a compound having the following structure: TIFF0007693229000004.tif14128, or a salt, solvate, geometric isomer, or stereoisomer thereof, In the formula, each R 9 is independently selected from the group consisting of hydrogen, halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and p is 0, 1, 2, 3, 4, or 5.

[0008] In some embodiments, another method of making a compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof, is to react a compound of formula I-SM, or a salt, solvate, geometric isomer, or stereoisomer thereof, with a compound of formula MX2(A-N(H)(R 5 ))2 in a solvent. In some embodiments, this reaction step is carried out in the presence of a base. The compound of formula I-SM can be a stable salt of any of the NHC moieties described herein. [Invention 1001] A compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof: TIFF0007693229000006.tif60128 Wherein, TIFF0007693229000007.tif2128 is a single bond or a double bond; R 1 and R 2 are each independently C 3~10 cycloalkyl, aryl, or heteroaryl, each of which is halogen, OR, SiR 3 , OSiR 3, OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, O C 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and may be substituted with at least one group selected from the group consisting of; R 3 and R 4 are each independently hydrogen, optionally substituted C 3~10 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C 1~12 alkyl, O C 1~12 alkyl, wherein any substitution is halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12alkyl, C 1~12 heteroalkyl, O C 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and contains at least one group selected from the group consisting of; or, R 3 and R 4 are used, together with the ring to which they are attached, to form C 4~20 cycloalkyl, C 6~20 aryl, or C 6~20 heteroaryl, each of which is halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, O C 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and may be substituted with at least one group selected from the group consisting of; R 5 is H or optionally substituted C 1~3 alkyl; M is a transition metal; X is a counteranion; A is C 6~18 aryl or C 6~18It is heteroaryl and is substituted with at least one group selected from the group consisting of halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, O C 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl; each R is independently hydrogen or optionally substituted C 1~10 alkyl; m is 1, 2, or 3; n is 1, 2, 3, or 4. [Inventive Item 1002] The compound of Inventive Item 1001, or a salt, solvate, geometric isomer, or stereoisomer thereof, having the following structure: TIFF0007693229000008.tif53128 [Inventive Item 1003] The compound of Inventive Item 1001, wherein R 1 and R 2 are both aryl. [Inventive Item 1004] The aryl is TIFF0007693229000009.tif28128 , where in the formula , R 6and R 7 are each independently C 1~12 alkyl, or C 1~12 alkyl substituted with at least one aryl; R 8 is hydrogen, or C 1~12 alkyl, or C 1~12 alkyl substituted with at least one aryl, The compound of Inventive Item 1003. [Inventive Item 1005] R 8 The compound of Inventive Item 1004, wherein is hydrogen. R 6 [Inventive Item 1006] 7 The compound of Inventive Item 1005, wherein 1~6 and R are each C R 6 alkyl. 7 [Inventive Item 1007] 3 ) 2 The compound of Inventive Item 1005, wherein and R are each C(H)(CH . [Inventive Item 1008] The compound of Inventive Item 1001, wherein M is selected from the group consisting of Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, and Au. [Inventive Item 1009] 2 The compound of Inventive Item 1008, wherein M is Pd. 3 [Inventive Item 1010] The compound of Inventive Item 1001, wherein X is selected from the group consisting of F, Cl, Br, I, OSO R, OSO TIFF0007693229000010.tif65134 R, and OC(=O)R. R 1 [Inventive Item 1011] TIFF0007693229000011.tif22128 The compound of Inventive Item 1010, wherein the N - heterocyclic carbene (NHC) moiety of the compound of formula I is selected from the group consisting of: R 6In the formula, 2 is selected from the group consisting of t - Bu, 1 - adamantyl, cyclohexyl, i - Pr, methyl, ethyl, n - propyl, butyl, pentyl, and 2 ; 2 is CH(phenyl) 2 , CH(Me) R 6' , CH(2 - Np) 2 , or CH(Et) 2 ; is CH(phenyl) , CH(Me) , or CH(Et). R 8 is CH(phenyl) 2 , Me, OMe, or H. [Inventive Concept 1012] The NHC moiety of the compound of formula I is selected from the group consisting of the following TIFF0007693229000012.tif240158 The compound of Inventive Concept 1001. [Inventive Concept 1013] The compound of Inventive Concept 1001, wherein n is 2. [Inventive Concept 1014] A is TIFF0007693229000013.tif12128 , and wherein each R 9 is independently selected from the group consisting of OCH 3 , CF 3 , 2,6-dimethyl, 2,6-di-isopropyl, and hydrogen, and p is 0, 1, 2, 3, 4, or 5, The compound of Inventive Concept 1001. [Inventive Concept 1015] R 5 The compound of Inventive Concept 1001, wherein is hydrogen or methyl. [Inventive Concept 1016] To form the compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof, with a compound having the following structure: TIFF0007693229000014.tif57128 or a salt, solvate, geometric isomer, or stereoisomer thereof, and a compound having the following structure: TIFF0007693229000015.tif14128 or a salt, solvate, geometric isomer, or stereoisomer thereof in a step of contacting in a solvent, wherein each R 9 is independently hydrogen, halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2, B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12 alkylalkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and p is 0, 1, 2, 3, 4, or 5, the step A method for preparing the compound of Inventive Concept 1001, comprising. [Inventive Concept 1017] The method of Inventive Concept 1016, wherein the solvent is a nonpolar aprotic solvent. [Inventive Concept 1018] The method of Inventive Concept 1017, wherein the solvent comprises chloroform, diethyl ether, deuterated chloroform, pentane, hexane, benzene, toluene, dichloromethane, or a mixture thereof. [Inventive Concept 1019] The method of Inventive Concept 1016, wherein the contacting is carried out at room temperature. [Inventive Concept 1020] To form the compound of formula I, with a compound having the following structure: TIFF0007693229000016.tif26128 or a salt, solvate, geometric isomer, or stereoisomer thereof, and a compound of formula MX 2 (A-N(H)(R 5 )) 2 or a salt, solvate, geometric isomer, or stereoisomer thereof in a step of contacting in a solvent A method for preparing the compound of Inventive Concept 1001, comprising. [Inventive Concept 1021] The method of Inventive Concept 1021, wherein the contacting is carried out in the presence of a base. [The present invention 1022] The base is NaOC 1~4 alkyl, KOC 1~4alkyl, lithium diisopropylamide, sodium hexamethyldisilazide, LiC 1~4 alkyl, or a combination thereof, the method of the present invention 1021. [The present invention 1023] The method of the present invention 1021, wherein the solvent comprises a polar aprotic solvent. [The present invention 1024] The method of the present invention 1023, wherein the solvent comprises tetrahydrofuran, 2-N-methylpyrrolidone, dimethylformamide, acetonitrile, and combinations thereof. [The present invention 1025] A compound of formula II, or a salt, solvate, geometric isomer, or stereoisomer thereof: TIFF0007693229000017.tif50128 Wherein, R 5 is H or optionally substituted C 1~3 alkyl; R A 、R 6 , and R 7 are independently optionally substituted C 1~12 alkyl, optionally substituted C 1~12 heteroalkyl, optionally substituted OC 1~12 alkyl, optionally substituted C 3~12 cycloalkyl, optionally substituted C 6~18 aryl, optionally substituted C 6~18 heteroaryl, or C substituted with at least one aryl or heteroaryl 1~3 alkyl, wherein any substitution is halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12 alkyl, C 1~12heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and is a substitution by at least one group selected from the group consisting of; M is a transition metal; X is a counteranion; n is an integer from 1 to 4; Each R is independently hydrogen or optionally substituted C 1~10 alkyl. [The present invention 1026] A compound of formula III, or a salt, solvate, geometric isomer, or stereoisomer thereof: TIFF0007693229000018.tif49128 Wherein, R 5 is H or C 1~3 alkyl; R 6 、R 7 , and R 8 are independently optionally substituted C 1~12 alkyl, optionally substituted C 1~12 heteroalkyl, optionally substituted OC 1~12 alkyl, optionally substituted C 3~12 cycloalkyl, optionally substituted C 6~18 aryl, optionally substituted C 6~18 heteroaryl, or C substituted with at least one aryl or heteroaryl 1~3 alkyl, wherein any substitution is halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 substitution by at least one group selected from the group consisting of heteroaryl; G is absent or may be substituted C 1~12 alkyl, optionally substituted C 1~12 heteroalkyl, optionally substituted OC 1~12 alkyl, optionally substituted C 3~12 cycloalkyl, optionally substituted C 6~18 aryl, optionally substituted C 6~18 heteroaryl, or C substituted with at least one aryl or heteroaryl 1~3 alkyl, where any substitution is halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 substitution by at least one group selected from the group consisting of heteroaryl; M is a transition metal; X is a counteranion; Y is N or C; Z is N or C; n is an integer from 1 to 4; each R is independently hydrogen or optionally substituted C 1~10 alkyl, provided that both Y and Z are not C.

Brief Description of the Drawings

[0009] The drawings generally illustrate, by way of example and not limitation, various aspects of the present application.

[0010] [[Figure 1]] The structures of well-defined Pd(II) precatalysts with different disposable ligands are shown. [[Figure 2]] The X-ray crystal structures of complexes 6a (a) and 7a (b) are shown. Two figures: front view (top view); side view (bottom view). Hydrogen atoms are omitted for clarity, except for the atoms in the NHC backbone and the ArNH2 moiety. Selected bond lengths [Å] and bond angles [°] for (6a): Pd1-C1, 1.970(3); Pd1-N3, 2.109(2); Pd1-Cl1, 2.2997(9); Pd1-Cl2, 2.2990(9); C1-N1, 1.354(3); C1-N2, 1.358(3); C1-Pd1-N3, 175.5(1); N3-Pd1-Cl1, 87.59(6); N3-Pd1-Cl2, 90.51(6); C1-Pd1-Cl2, 90.54(8); N1-C1-N2, 105.3(2); N1-C1-Pd1, 124.2(2); N2-C1-Pd1, 130.4(2). For the selected bond lengths [Å] and bond angles [°] of (7a). [[Figure 3]] Topographic stereomaps of [(IPr)PdCl2(AN)] (6a) and [(SIPr)PdCl2(AN)] (7a) showing % Vbur per quadrant are shown. [[Figure 4]] Figures 4A - 4B show the X-ray crystal structure of IPr#-PEPPSI, [Pd(IPr#)(3-Cl-py)Cl2], in a front view (Figure 4A) and a side view (Figure 4B).

DETAILED DESCRIPTION OF THE INVENTION

[0011] DETAILED DESCRIPTION OF THE INVENTION The synthesis, characterization, and reactivity of [(NHC)PdCl2(aniline)] complexes that meet the criteria of an ideal catalyst are described herein. In certain non-limiting embodiments, unexpected features of the catalysts herein include Suzuki-Miyaura cross-coupling of amides by N-C(O) activation, as well as well-defined Suzuki-Miyaura cross-coupling of esters with aryl chlorides and Buchwald-Hartwig amination, air and moisture stability, and high activity. In the compounds herein, widely available anilines are used as disposable ligands for well-defined Pd(II)-NHC catalysis. The availability of various aniline skeletons, including those with structural and electronic diversity, provides advantages in the design and fine-tuning of difficult cross-coupling reactions.

[0012] Reference will now be made in detail to specific embodiments of the disclosed subject matter, examples of which are illustrated in the accompanying drawings. The disclosed subject matter will be described in connection with numbered claims, but it should be understood that the illustrated subject matter is not intended to limit the disclosed subject matter to the claimed subject matter.

[0013] Throughout this document, values expressed in the form of a range are to be construed flexibly as including not only the numerical values explicitly recited as the limits of the range, but also all individual numerical values or sub-ranges subsumed within that range as if each such numerical value and sub-range were explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" is to be construed to include not only about 0.1% to about 5%, but also the individual values within the indicated range (e.g., 1%, 2%, 3%, and 4%) and sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise indicated, a recitation of "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise indicated, a recitation of "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0014] In this document, unless the context clearly indicates otherwise, the terms "a", "an", or "the" are used to include one or more than one. Unless otherwise indicated, the term "or" is used to mean a non-exclusive "or". A recitation of "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B". Further, phrases or terms used herein and not otherwise defined are to be understood as being for descriptive purposes only and not for purposes of limitation. Any use of section headings is intended to aid in the reading of the document and is not to be construed as limiting. Information related to a section heading may occur inside or outside of that particular section. All publications, patents, and patent documents referred to in this document are hereby incorporated by reference in their entirety as if each were individually incorporated by reference.

[0015] In the methods described herein, acts can be performed in any order, except where a temporal or operational order is explicitly recited. Further, acts can be performed simultaneously, unless the explicit language of the claim states that the particular acts must be performed separately. For example, the acts recited in a claim of performing X and the acts recited in a claim of performing Y can be performed simultaneously within one operation, and the resulting process is within the literal scope of the claimed process.

[0016] Definition As used herein, the term "about" can permit variation of a value or range of values within, for example, 10%, 5%, or 1% of a recited value or the recited limit of a range, and includes the exact value or range recited.

[0017] As used herein, the term "substantially" means "a majority of" or "mostly", at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term "substantially free of" may mean having none at all or having a negligible amount, and thus the amount of the material present does not affect the material properties of the composition containing the material, and thus the material is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than about 4.5 wt%, equivalent to about 4.5 wt%, or more than about 4.5 wt%, or 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of" may mean having a negligible amount, and thus the material is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than about 4.5 wt%, equivalent to about 4.5 wt%, or more than about 4.5 wt%, or 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

[0018] As used herein, the term "organic group" means any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups; carboxyl groups including carboxylic acids, carboxylates, and carboxylic acid esters; sulfur-containing groups such as alkyl sulfide and aryl sulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C 100 )hydrocarbyl, where R can be hydrogen (in examples containing other carbon atoms) or a carbon-based moiety, and the carbon-based moiety may or may not be substituted.

[0019] As used herein with respect to a molecule or organic group defined herein, the term "substituted" means that one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. As used herein, the term "functional group" or "substituent" means a group capable of effecting or effecting substitution on a molecule or organic group. Examples of substituents or functional groups include halogen (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxy group, alkoxy group, aryloxy group, aralkyloxy group, oxo (carbonyl) group, carboxyl group including carboxylic acid, carboxylate, and carboxylic acid ester; sulfur atoms in thiol group, alkyl sulfide group and aryl sulfide group, sulfoxide group, sulfone group, sulfonyl group, and sulfonamide group; nitrogen atoms in groups such as amine, hydroxyamine, nitrile, nitro group, N-oxide, hydrazide, azide, and enamine; and other heteroatoms in various other groups, but are not limited thereto. Non-limiting examples of substituents capable of bonding to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, where R can be hydrogen or a carbon-based moiety. For example, R is hydrogen, (C1-C 100)It can be hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to a nitrogen atom or multiple adjacent nitrogen atoms can together with one or more of said nitrogen atoms form a heterocyclyl.

[0020] As used herein, the term "alkyl" means straight-chain and branched alkyl groups, as well as cycloalkyl groups having from 1 to 40 carbon atoms, from 1 to about 20 carbon atoms, from 1 to 12 carbon atoms, or in some embodiments from 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include groups having from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The term "alkyl" as used herein encompasses n-alkyl groups, isoalkyl groups, and anteisoalkyl groups, as well as other branched-chain forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups listed herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0021] As used herein, the term "alkenyl" means a straight-chain, branched-chain, and cyclic alkyl group as defined herein, except that at least one double bond is present between two carbon atoms. Thus, an alkenyl group has from 2 to 40 carbon atoms, or from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments from 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0022] As used herein, the term "alkynyl" means a straight-chain and branched-chain alkyl group as defined herein, except that at least one triple bond is present between two carbon atoms. Thus, an alkynyl group has from 2 to 40 carbon atoms, from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments from 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3).

[0023] As used herein, the term "acyl" means a group containing a carbonyl moiety bonded through a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or to another carbon atom which may be part of an alkyl group, aryl group, aralkyl group, cycloalkyl group, cycloalkylalkyl group, heterocyclyl group, heterocyclylalkyl group, heteroaryl group, heteroarylalkyl group, etc. The acyl group may contain from 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain double or triple bonds within the scope of the meaning herein. An acryloyl group is an example of an acyl group. The acyl group may contain heteroatoms within the scope of the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the scope of the meaning herein. Other examples include an acetyl group, benzoyl group, phenylacetyl group, pyridylacetyl group, cinnamoyl group, and acryloyl group. When a group containing a carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is the trifluoroacetyl group.

[0024] As used herein, the term "cycloalkyl" means a cyclic alkyl group such as, but not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. In some embodiments, the cycloalkyl group can have from 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Further, examples of cycloalkyl groups include, but are not limited to, polycyclic cycloalkyl groups such as a norbornyl group, an adamantyl group, a bornyl group, a camphenyl group, an isocamphenyl group, and a carenyl group, and fused rings such as, but not limited to, a decalinyl group. The cycloalkyl group also includes rings substituted with a linear or branched alkyl group as defined herein. Representative substituted cycloalkyl groups include, but are not limited to, monosubstituted or polysubstituted groups such as a 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl group or a monosubstituted, disubstituted, or trisubstituted norbornyl group or cycloheptyl group, which may be substituted, for example, with an amino group, a hydroxy group, a cyano group, a carboxy group, a nitro group, a thio group, an alkoxy group, and a halogen group. The term "cycloalkenyl" alone or in combination means a cyclic alkenyl group.

[0025] As used herein, the term "aryl" means a cyclic aromatic hydrocarbon group that does not contain a heteroatom in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylene, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains from about 6 to about 14 carbons in the ring portion of the group. The aryl group may be unsubstituted or substituted as defined herein. Representative substituted aryl groups include, but are not limited to, phenyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or naphthyl groups substituted at any one or more of the 2- to 8-positions thereof, and may be mono-substituted or substituted two or more times.

[0026] As used herein, the term "aralkyl" means an alkyl group as defined herein in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, and fused (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined herein in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0027] As used herein, the term "heterocyclyl" means aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. Thus, heterocyclyl can be cycloheteroalkyl, or heteroaryl, or, if polycyclic, any combination thereof. In some embodiments, the heterocyclyl group contains from 3 to about 20 ring members, while other similar groups have from 3 to about 15 ring members. A heterocyclyl group called C2-heterocyclyl can be a 5-membered ring having 2 carbon atoms and 3 heteroatoms, a 6-membered ring having 2 carbon atoms and 4 heteroatoms, and the like. Similarly, C4-heterocyclyl can be a 5-membered ring having 1 heteroatom, a 6-membered ring having 2 heteroatoms, and the like. The number of carbon atoms and the number of heteroatoms are equal to the total number of ring atoms. The heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is one embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including species containing fused aromatic and non-aromatic groups. For example, both a dioxolanyl ring and a benzodioxolanyl ring system (methylenedioxyphenyl ring system) are heterocyclyl groups within the scope of the meaning herein. This phrase also includes polycyclic systems containing heteroatoms, such as, but not limited to, quinuclidyl. The heterocyclyl group may or may not be substituted and may be substituted as described herein.Examples of the heterocyclic group include, but are not limited to, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, pyrrolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyridinyl group, thiophenyl group, benzothiophenyl group, benzofuranyl group, dihydrobenzofuranyl group, indolyl group, dihydroindolyl group, azaindolyl group, indazolyl group, benzimidazolyl group, azabenzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzothiadiazolyl group, imidazopyridinyl group, isoxazolopyridinyl group, thianaphthalenyl group, purinyl group, xanthinyl group, adeninyl group, guanylinyl group, quinolinyl group, isoquinolinyl group, tetrahydroquinolinyl group, quinoxalinyl group, and quinazolinyl group. Representative substituted heterocyclic groups can be groups such as a monosubstituted or polysubstituted piperidinyl group or quinolinyl group, etc., and are not limited thereto, and these can be 2-, 3-, 4-, 5- or 6-substituted or disubstituted with groups such as the groups listed in this specification.

[0028] As used herein, the term "heteroaryl" means an aromatic ring compound containing 5 or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. For example, a heteroaryl ring can have from 5 to about 8-12 ring members. A heteroaryl group is a variety of heterocyclyl groups having an aromatic electronic structure. A heteroaryl group called C2-heteroaryl can be a 5-membered ring having 2 carbon atoms and 3 heteroatoms, a 6-membered ring having 2 carbon atoms and 4 heteroatoms, and the like. Similarly, C4-heteroaryl can be a 5-membered ring having 1 heteroatom, a 6-membered ring having 2 heteroatoms, and the like. The total number of carbon atoms and heteroatoms is equal to the total number of ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guanylinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. The heteroaryl group may be unsubstituted or may be substituted with the groups described herein. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those listed herein.

[0029] Further examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepin (5H-dibenzo[b,f]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H-dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepin (10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,Examples include, but are not limited to, (azepin-5-yl).

[0030] As used herein, the term "heterocyclylalkyl" means an alkyl group as defined herein where a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0031] As used herein, the term "heteroarylalkyl" means an alkyl group as defined herein where a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0032] As used herein, the term "alkoxy" means an oxygen atom connected to an alkyl group containing a cycloalkyl group as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc. Examples of branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, etc. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. An alkoxy group can contain from about 1 to about 12, from about 1 to about 20, or from about 1 to about 40 carbon atoms attached to the oxygen atom, can further contain double or triple bonds, and can also contain heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the scope of the meaning herein, and in the context where two adjacent atoms of the structure are substituted thereby, a methylenedioxy group is also so.

[0033] As used herein, the term "amine" means primary, secondary, and tertiary amines having, for example, the formula N(group)3 where each group can independently be H or non-H such as alkyl or aryl. Amines include R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and R3N where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc., but are not limited thereto. The term "amine" also includes ammonium ions as used herein.

[0034] As used herein, the term "amino group" means substituents of the forms -NH2, -NHR, -NR2, -NR3 where each R is independently selected, + and the protonated forms of each form except for -NR3 which cannot be protonated. Thus, any compound substituted with an amino group can be regarded as an amine. An "amino group" within the scope of meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino groups, dialkylamino groups, and trialkylamino groups. +

[0035] As used herein, the term "halo", "halogen", or "halide" group, either by itself or as part of another substituent, means a fluorine atom, chlorine atom, bromine atom, or iodine atom, unless otherwise specified.

[0036] As used herein, the term "haloalkyl" group includes mono-haloalkyl groups, poly-haloalkyl groups where all the halo atoms may be the same or different, and per-haloalkyl groups where all the hydrogen atoms are replaced by halogen atoms such as fluorine. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0037] As used herein, the term "monovalent" means that the substituent is connected to the substituted molecule by a single bond. When the substituent is monovalent, e.g., F or Cl, the substituent is bonded by a single bond to the atom it is substituting.

[0038] As used herein, the term "hydrocarbon" or "hydrocarbyl" means a molecule or functional group containing carbon and hydrogen atoms. This term usually includes both carbon and hydrogen atoms, but may also mean a molecule or functional group in which all the hydrogen atoms are substituted by other functional groups.

[0039] As used herein, the term "hydrocarbyl" means a functional group derived from a straight-chain, branched, or cyclic hydrocarbon and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. The hydrocarbyl group may be represented as (C a ~C b )hydrocarbyl, where a and b are integers and mean having any number of carbon atoms from a to b. For example, (C1-C4)hydrocarbyl means that the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-C b )hydrocarbyl means that in certain embodiments, no hydrocarbyl group is present. In certain embodiments, the hydrocarbyl may be optionally substituted C 1~12is alkyl. In certain embodiments, the hydrocarbyl is optionally substituted C 2~12 is alkenyl. In certain embodiments, the hydrocarbyl is optionally substituted C 2~12 is alkynyl. In certain embodiments, the hydrocarbyl is optionally substituted C 3~12 is cycloalkyl. In certain embodiments, the hydrocarbyl is optionally substituted C 1~12 is heteroalkyl. In certain embodiments, the hydrocarbyl is optionally substituted C 1~12 is alkoxy. In certain embodiments, the hydrocarbyl is optionally substituted C 6~14 is aryl, and / or optionally substituted C 6~12 is aryl, and / or optionally substituted C 6~10 is aryl. In certain embodiments, the hydrocarbyl is optionally substituted C2-C 12 is heterocyclyl. In certain embodiments, the hydrocarbyl is optionally substituted C4-C 12 is heteroaryl. In certain embodiments, the hydrocarbyl is optionally substituted C 1~12 is acyl.

[0040] As used herein, the term "solvent" means a liquid capable of dissolving a solid, liquid, or gas. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0041] As used herein, the term "independently selected from" means that, unless the context clearly indicates otherwise, the groups referred to are the same group, different groups, or mixtures thereof. Thus, based on this definition, the phrase "X 1 , X 2 , and X 3 are independently selected from the noble gases" means, for example, the situation where X 1 , X 2 , and X 3 are all the same, the situation where X 1 , X 2 , and X 3the situation where all are different, X 1 and X 2 are the same but X 3 is different, and other similar permutation situations will be included.

[0042] As used herein, the term "room temperature" means a temperature of about 15°C to 28°C.

[0043] As used herein, the terms "standard temperature" and "standard pressure" mean 20°C and 101 kPa.

[0044] As used herein, the term "composition" or "pharmaceutical composition" means a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. There are multiple techniques in the art for administering the compound, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, pulmonary administration, and topical administration.

[0045] As used herein, the abbreviation "Np" means naphthyl. Thus, 1-Np is 1-naphthyl and 2-Np is 2-naphthyl.

[0046] Preparation of Compounds The compounds of formula I or the compounds otherwise described herein can be prepared by the general schemes described herein using synthetic methods known to those skilled in the art. The following examples illustrate non-limiting aspects of the compounds described herein and their preparation.

[0047] In various aspects, the present disclosure provides a compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof: TIFF0007693229000019.tif59128wherein, TIFF0007693229000020.tif2128is a single bond or a double bond; R 1 and R2 is independently C 3~10 cycloalkyl, aryl, or heteroaryl, each of which is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and may be substituted with at least one group selected from the group consisting of; R 3 and R 4 are each independently hydrogen, optionally substituted C 3~10 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, C 1~12 alkyl, or OC 1~12 alkyl, wherein any substitution is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and contains at least one group selected from the group consisting of; or, R 3 and R 4 together with the ring to which they are attached, C4~20 Cycloalkyl, C 6~20 Aryl, or C 6~20 Heteroaryl, which are each used to form halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 Alkyl, C 1~12 Heteroalkyl, OC 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, and C 6~10 May be substituted with at least one group selected from the group consisting of heteroaryl; R 5 Is H or optionally substituted C 1~3 Alkyl; M is a transition metal; X is a counteranion; A is aryl or heteroaryl, halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 Alkyl, C 1~12 Heteroalkyl, OC 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, and C 6~10 May be substituted with at least one group selected from the group consisting of heteroaryl; Each R is independently hydrogen or optionally substituted C 1~10 Alkyl; m is 1, 2, or 3; n is 1, 2, 3, or 4.

[0048] The nature of the variable element A in the compound of formula I is not particularly limited, provided that a stable complex with a transition metal can be formed by the ligands described herein and the resulting transition metal complex has catalytic activity. Other suitable A moieties include anthracene (e.g., 1-aminoanthracene, 2-aminoanthracene, 9-aminoanthracene); aminobiphenyl (e.g., 4-aminobiphenyl); aminophenanthrene (e.g., 1-aminophenanthrene, 2-aminophenanthrene, 9-aminophenanthrene); aminopyrene (e.g., 1-aminopyrene, 2-aminopyrene); aminochrysene (e.g., 1-aminochrysene, 2-aminochrysene, 6-aminochrysene); aminofluorene (e.g., 1-aminofluorene, 2-aminofluorene); naphthalene (e.g., 1-aminonaphthalene, 2-aminonaphthalene); acridine (e.g., 9-aminoacridine, 2-aminoacridine); quinoline (e.g., 8-aminoquinoline, 2-aminoquinoline, 5-aminoquinoline); and the like. Any arylamine or heteroarylamine described herein can be a primary amine or a secondary amine.

[0049] In some embodiments, the compound has the structure of formula Ia, or a salt, solvate, geometric isomer, or stereoisomer thereof. TIFF0007693229000021.tif52128

[0050] In some embodiments, the compound has the structure of formula Ib, formula Ic, formula Id, formula Ie, or formula If, or a salt, solvate, geometric isomer, or stereoisomer thereof. TIFF0007693229000022.tif172128

[0051] In some embodiments, R 1 and R 2 are both aryl. In various embodiments, the aryl group has the following structure: TIFF0007693229000023.tif having 28128, or a salt, solvate, geometric isomer, or stereoisomer thereof, wherein R 6 and R 7 are each independently C 1~12 alkyl, or C 1~12 alkyl substituted with at least one aryl; R 8 is hydrogen, or C 1~12 alkyl, or C 1~12 alkyl substituted with at least one aryl.

[0052] In some embodiments, R 8 is hydrogen. In various embodiments, R 6 and R 7 are each C 1~6 alkyl. In some embodiments, R 6 and R 7 are each C(H)(CH3)2. In various embodiments, M is selected from the group consisting of Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, and Au. In some embodiments, M is Pd. In various embodiments, X is selected from the group consisting of F, Cl, Br, I, OSO2R, OSO3R, and OC(=O)R. In some embodiments, X is Cl. In various embodiments, m is 1. In various embodiments, n is 2.

[0053] In some embodiments, A is TIFF0007693229000024.tif 12128; each R 9 is independently selected from the group consisting of OCH3, CF3, 2,6-dimethyl, 2,6-di-isopropyl, and hydrogen, and p is 0, 1, 2, 3, 4, or 5. In some embodiments, R 5 is hydrogen or methyl.

[0054] The compound of formula I has the three moieties shown below. TIFF0007693229000025.tif43128

[0055] In various embodiments, the NHC moiety in the compound of formula I is selected from the group consisting of: TIFF0007693229000026.tif65134wherein, R 1 is selected from the group consisting of t-Bu, 1-adamantyl, cyclohexyl, i-Pr, methyl, ethyl, n-propyl, butyl, pentyl, and TIFF0007693229000027.tif22128; R 6 is CH(phenyl)2, CH(Me)2, CH(2-Np)2, or CH(Et)2; R 6' is CH(phenyl)2, CH(Me)2, or CH(Et); R 8 is CH(phenyl)2, Me, OMe, or H.

[0056] In various embodiments, the NHC moiety in the compound of formula I is as follows: TIFF0007693229000028.tif202157and TIFF0007693229000029.tif34128is selected from the group consisting of;

[0057] In various embodiments, a method for preparing a compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof, is provided. The method comprises contacting a compound having the following structure: TIFF0007693229000030.tif57128or a salt, solvate, geometric isomer, or stereoisomer thereof, with a compound having the following structure: TIFF0007693229000031.tif14128or a salt, solvate, geometric isomer, or stereoisomer thereof in a solvent, wherein each R 9independently, hydrogen, halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and p is 0, 1, 2, 3, 4, or 5.

[0058] In various embodiments, the solvent is a nonpolar aprotic solvent. Suitable nonpolar aprotic solvents include, but are not limited to, chloroform, diethyl ether, deuterated chloroform, pentane, hexane, benzene, toluene, dichloromethane, or mixtures thereof. In some embodiments, the contact is carried out at room temperature.

[0059] In some embodiments, another method of making a compound of Formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof, is to form a compound of Formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof, by contacting a compound of Formula I-SM, or a salt, solvate, geometric isomer, or stereoisomer thereof, with a compound of Formula MX2(A-N(H)(R 5 ))2, or a salt, solvate, geometric isomer, or stereoisomer thereof, in a solvent. In some embodiments, this reaction step is carried out in the presence of a base. The compound of Formula I-SM can be a stable salt of any of the NHC moieties described herein.

[0060] Suitable bases include NaOC 1~4 alkyl, KOC 1~4Alkyl, lithium diisopropylamide, sodium hexamethyldisilazide, LiC 1~4 Examples include, but are not limited to, alkyl, or combinations thereof. In some embodiments, the reaction using the base is carried out in a polar aprotic solvent. Suitable polar aprotic solvents include, but are not limited to, tetrahydrofuran, 2-N-methylpyrrolidone, dimethylformamide, acetonitrile, or mixtures thereof.

[0061] In various embodiments, the compound is a compound of Formula II, or a salt, solvate, geometric isomer, or stereoisomer thereof. TIFF0007693229000033.tif50128

[0062] In the compound of Formula II, X and “n” are as defined herein.

[0063] R A 、R 6 、and R 7 are each independently optionally substituted C 1~12 alkyl, optionally substituted C 1~12 heteroalkyl, optionally substituted OC 1~12 alkyl, optionally substituted C 3~12 cycloalkyl, optionally substituted C 6~10 aryl, optionally substituted C 6~10 heteroaryl, A, R 1 、or R 2 is selected from. R 6 and R 7 Any optional substitution in is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12Heteroalkyl, OC 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, and C 6~10 It is at least one group selected from the group consisting of heteroaryl.

[0064] In various embodiments, the present compound is a compound of formula III, or a salt, solvate, geometric isomer, or stereoisomer thereof. TIFF0007693229000034.tif48128

[0065] In the compound of formula III, X, n, R 6 , and R 7 are as defined herein. The variable element R 8 is defined in the same manner as R 6 . The variable element Y is N or C, and Z is N or C, provided that both Y and Z cannot be C. G is absent or is defined in the same manner as R 6 . The compound of formula III is a mesoionic carbene complex.

[0066] The compound of formula III can be formed, for example, by the following reaction. TIFF0007693229000035.tif69128

[0067] In various embodiments, the present compound is a mesoionic carbene complex selected from the group consisting of the following TIFF0007693229000036.tif49162.

[0068] The compounds described herein may have one or more stereocenters, and each stereocenter may independently exist in the (R) configuration or the (S) configuration. In certain embodiments, the compounds described herein exist as optically active forms or racemates. It should be understood that the compounds described herein include racemates, optically active forms, positional isomers, and stereoisomers, or combinations thereof, having the therapeutically useful properties described herein. The preparation of optically active forms is achieved in any suitable manner including, by way of non-limiting example, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is utilized as the therapeutic compounds described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of compounds and their isomers is effected by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0069] The methods and formulations described herein include the use of N-oxides (where appropriate), crystal forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any of the compounds described herein, as well as metabolites and active metabolites of these compounds that exhibit the same kind of activity. Solvates include solvates with water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohols (e.g., ethanol), and acetate esters, among others. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated forms.

[0070] In certain embodiments, the compounds described herein may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0071] In certain embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" means a drug that is converted in vivo to the parent drug. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the present compound. In other embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the present compound by one or more steps or processes.

[0072] In certain embodiments, sites on, for example, the aromatic ring moiety of the compounds described herein are susceptible to various metabolic reactions. By incorporating suitable substituents on the aromatic ring structure, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, deuterium, halogen, or alkyl groups.

[0073] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced with an atom having an atomic mass or atomic mass number different from the atomic mass or atomic mass number usually found in nature while having the same number of atoms. Examples of isotopes preferably included in the compounds described herein are 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S, among others. In certain embodiments, the isotopically labeled compounds are useful in drug distribution studies and / or substrate tissue distribution studies. In other embodiments, substitution with heavy isotopes such as deuterium results in increased metabolic stability (e.g., increased in vivo half-life or decreased required dosage). In yet other embodiments, 11C, 18 F, 15 O, and 13 substitution with positron-emitting isotopes such as N is useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. The isotopically labeled compounds are prepared by any suitable method or by a process that uses a suitable isotopically labeled reagent in place of the unlabeled reagent used separately.

[0074] In certain embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of a chromophore or fluorophore, a bioluminescent label, or a chemiluminescent label.

[0075] The compounds described herein, and other related compounds having different substituents, can be prepared using the techniques and materials described herein and Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 thThey are synthesized, for example, as described in March, Advanced Organic Chemistry 5th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001) and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), the disclosures of which are incorporated herein by reference. General methods for the preparation of the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various moieties found in the formulas shown herein.

[0076] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or are prepared using the procedures described herein.

[0077] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxy groups are protected to avoid their unwanted participation in the reaction. Protecting groups are used to block some or all of the reactive moieties to prevent the group from participating in the chemical reaction until the protecting group is removed. In other embodiments, each protecting group is removable by different means. The need for differential removal is satisfied by protecting groups that cleave under completely different reaction conditions.

[0078] In certain embodiments, the protecting group is removed by an acid, a base, reductive conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid-labile, and are used to protect carboxy-reactive and hydroxy-reactive moieties in the presence of an amino group protected with a Cbz group removable by hydrogenolysis and an amino group protected with a base-labile Fmoc group. The carboxylic acid-reactive and hydroxy-reactive moieties are blocked with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of an amine blocked with an acid-labile group such as t-butyl carbamate, or are blocked with a carbamate that is acid-stable and base-stable but removable by hydrolysis.

[0079] In certain embodiments, the carboxylic acid-reactive and hydroxy-reactive moieties are blocked with a protecting group removable by hydrolysis such as a benzyl group, while an amine group capable of hydrogen bonding with an acid is blocked with a base-labile group such as Fmoc. The carboxylic acid-reactive moiety is protected by conversion to a simple ester compound exemplified herein including conversion to an alkyl ester, or is blocked with a protecting group removable by oxidation such as 2,4-dimethoxybenzyl, while an amino group present simultaneously is blocked with a fluoride-labile silyl carbamate.

[0080] An allyl blocking group is useful in the presence of acid and base protecting groups. This is because the former is stable and is subsequently removed by a metal catalyst or a π-acid catalyst. For example, an allyl-blocking carboxylic acid is deprotected by a palladium-catalyzed reaction in the presence of an acid-labile t-butyl carbamate or a base-labile acetate amine protecting group. Yet another form of a protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, its functional group is blocked and does not react. When released from the resin, the functional group becomes available for reaction.

[0081] Typically, the blocking / protecting group can be selected from the following. TIFF0007693229000037.tif80137

[0082] Other protecting groups, in conjunction with a detailed description of the techniques applicable to the creation and removal of protecting groups, are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference.

Examples

[0083] By referring to the following examples provided by way of illustration, various aspects of the present application can be better understood. The scope of the present application is not limited to the examples shown below.

[0084] In recent years, several well-defined stable precatalysts have emerged (Figure 1, 1 - 5). The stabilization of palladium by amine-type nitrogen is a major feature of the Nolan and Buchwald paradicycles (Figure 1, 4 - 5). The synthesis of compounds of Formula I, such as [(NHC)PdCl2(aniline)] complexes, is shown in Scheme 1. Since IPr is a privileged motif in Pd-NHC catalysis (6), it was selected as a model NHC ancillary ligand. Furthermore, a representative imidazolinylidene complex Pd-SIPr was synthesized (7). The synthesis of [(NHC)PdCl2(aniline)] complexes was readily achieved in excellent yields by reacting aniline with the [{Pd(NHC)(Cl)(μ-Cl)}2] dimer in CH2Cl2 at room temperature. After trituration with cold pentane, the [(NHC)PdCl2(aniline)] complexes were isolated. All complexes were found to be stable towards air and moisture. It should be noted that if desired, the [(NHC)PdCl2(aniline)] complexes may be subjected to chromatographic purification, which should facilitate their use. Complexes 6a and 7a were fully characterized by X-ray crystallographic analysis (Figure 2, see below). Considering the utility of the PdCl2(aniline)2 precursor for the rapid screening of various NHCs, the direct synthesis of [(IPr)PdCl2(AN)] (AN = aniline) (Scheme 2) was developed. In some embodiments, a well-defined [(IPr)PdCl2(AN)] complex is obtained in 70% yield by reacting IPrHCl (1.5 equiv) with Pd(PhNH2)2Cl2 (1.0 equiv) and KOt-Bu (1.5 equiv) in THF at 80 °C.

[0085] As shown in Figs. 2A - 2B, complexes 6a and 7a adopt a slightly distorted square planar geometry (6a: C - Pd - N, 175.5°; 7a: C - Pd - N, 175.3°). The C - Pd bond lengths and Pd - N bond lengths are 1.970 Å and 2.109 Å in 6a, and 1.967 Å and 2.116 Å in 7a, respectively. The Cl1 - Pd bond lengths and Cl2 - Pd bond lengths are 2.2997 Å and 2.2990 Å in 6a (Cl1 - Pd - Cl2, 175.8°), and 2.299 Å and 2.285 Å in 7a (Cl1 - Pd - Cl2, 174.7°), respectively. These bond lengths are within the same range as those of Pd(NHC)(heterocycle)Cl2 complexes. From this, it is inferred that the availability of aniline enables a direct approach to modulating the steric and electronic effects on the metal center in the [(NHC)PdCl2(aniline)] complex.

[0086] To evaluate the steric effects in the [(NHC)PdCl2(aniline)] complex, the buried volume % (%V bur ) and steric maps for 6a and 7a were calculated (Fig. 3). Since (%V bur ) are 36.1% and 39.7%, respectively, 6a and 7a are bulky [Pd - NHC] complexes. These values can be compared with the (%V bur ) of 34.8% and 39.2% for the [Pd(IPr)(3 - Cl - py)Cl2] complex and [Pd(SIPr)(3 - Cl - py)Cl2] complex. As expected, the use of the asymmetric aniline disposable ligand results in a non - uniform quadrant distribution of 30.7%, 41.0%, 36.9%, 35.9% (6a) and 35.4%, 44.5%, 37.3%, 41.6% (7a) for each quadrant. The special steric environment around the metal may affect the substrate approach and catalytic activation in the [(NHC)PdCl2(aniline)] complex.

[0087] Scheme 1 Synthesis of (NHC)PdCl2(aniline) complex a TIFF0007693229000038.tif68128 aConditions: [{Pd(NHC)(Cl)(μ-Cl)}2] (1.0 equiv), aniline (2.0 equiv), CH2Cl2, 23 °C.

[0088] Scheme 2 Direct synthesis of (IPr)PdCl2(AN) a TIFF0007693229000039.tif43136 a Conditions: IPrHCl (1.5 equiv), PdCl2(AN)2 (1.0 equiv), KOt-Bu (1.5 equiv), THF, 80 °C. AN = PhNH2.

[0089] (NHC)PdCl2(aniline) complexes were directly obtained, and then the reactivity of these novel Pd(II)-NHC precatalysts was investigated. For the initial screening, Suzuki-Miyaura cross-coupling of amides by N-C(O) activation was selected (Table 1). Reactions carried out at 1.0 mol% of (IPr)PdCl2(aniline) using a series of electronically and sterically special precatalysts 6a - h (K2CO3, H2O, THF, 16 h) showed high reactivity in mild room-temperature cross-coupling (Table 1, column A). Thus, both the electron-neutral aniline ligand (6a), the electron-donating 4-anisidine (6b) and the electron-withdrawing 4-trifluoromethylaniline (6c), as well as the moderately sterically hindered 2,6-xylidine (6d) all gave cross-coupling products in quantitative yields under these conditions. The use of the more sterically bulky 2,6-diisopropylaniline (6e) decreased the efficiency of cross-coupling. The use of a meta-position electron-withdrawing trifluoromethyl group (6f), as well as N-Me-aniline (6g - h), and a representative NHC with a saturated backbone (SIPr)PdCl2(AN) (7a) gave cross-coupling products with excellent efficiency.

[0090] (Table 1) Activity of (NHC)PdCl2(aniline) complexes in Suzuki-Miyaura cross-coupling of amides TIFF0007693229000040.tif183166 a[Pd] (1.0 mol %), amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), K2CO3 (3.0 equiv), H2O (5.0 equiv), THF (0.25 M), 23 °C, 16 h. b [Pd] (0.25 mol %). c [Pd] (1.0 mol %), 3 h.

[0091] Next, the activity of these new precatalysts was discriminated by performing cross-coupling with a 0.25 mol % addition rate of (IPr)PdCl2(aniline) (Table 1, column B). In this more discriminatory screening, electronically neutral substituents (6a) and electron-withdrawing substituents (6c) were preferred over electron-donating substituents (6b), while the cross-coupling efficiency decreased due to steric hindrance in the aniline ring (6d - e). The meta-trifluoromethyl group (6f) and N-Me-aniline (6g - h) gave good results in this screening, while the saturated (SIPr)PdCl2(AN) (7a) was found to be relatively inefficient. To gain insights into the activation of these new precatalysts, the reaction was carried out with 1.0 mol % of (IPr)PdCl2(aniline) over a shorter reaction time (Table 1, column C, room temperature, 3 h). As shown in the table, high reaction efficiencies were obtained with electronically neutral (6a), electron-withdrawing (6b), and N-Me substitution (6g). Therefore, in this study, 3-trifluoromethylaniline (6f) was found to be the optimal ligand, and neutral aniline (6a) was found as an inexpensive variant that is readily available in large quantities.

[0092] The generality of the Suzuki - Miyaura cross-coupling using (IPr)PdCl2(AN) is shown in Table 2. As shown in the table, the reaction tolerated a wide range of functional groups and substituents in both the boronic acid and amide cross-coupling partners. Electron-donating substituents, electron-withdrawing substituents, and sterically hindered substituents were well tolerated in both coupling partners, and cross-coupling products were obtained in excellent yields.

[0093] (Table 2) [(IPr)PdCl2(AN)]-Catalyzed Suzuki - Miyaura Cross-Coupling of Amides with C-N Cleavagea TIFF0007693229000041.tif84164 a Conditions: [Pd] (1.0 mol%), amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), K2CO3 (3.0 equiv), H2O (5.0 equiv), THF (0.25 M), 23 °C, 16 h.

[0094] Suzuki-Miyaura cross-coupling of esters by C-O activation is also feasible using this novel catalyst system (Scheme 3). In some embodiments, in this relatively difficult C-O cross-coupling, the Pd-NHC catalyst having 3-trifluoromethylaniline (6f) is more efficient than the neutral aniline (6a) ligand, which reflects the trend of reactivity observed in amide C-N bond activation. To expand the utility of the (NHC)PdCl2(aniline) complex, the reactivity of (IPr)PdCl2(AN) in the Suzuki-Miyaura cross-coupling of aryl chlorides (Scheme 4 and Table 3) was investigated. As shown in the table, the reaction showed excellent tolerance. Cross-coupling products were obtained in excellent yields with aryl chlorides substituted with electron-donating functional groups, electron-withdrawing functional groups, and sterically hindered functional groups, as well as boronic acids having electron-donating substituents, electron-withdrawing substituents, and sterically hindered substituents.

[0095] Scheme 3 [(IPr)PdCl2(aniline)]-Catalyzed Suzuki-Miyaura Cross-Coupling of Esters by C-O Cleavage TIFF0007693229000042.tif26128

[0096] Scheme 4 [(IPr)PdCl2(aniline)]-Catalyzed Suzuki-Miyaura Cross-Coupling of Aryl Chlorides TIFF0007693229000043.tif26128

[0097] (Table 3) [(IPr)PdCl2(AN)]-Catalyzed Suzuki-Miyaura Cross-Coupling of Aryl Chlorides a TIFF0007693229000044.tif105164 a Conditions: [Pd] (1.0 mol%), aryl chloride (1.0 equiv), Ar-B(OH)2 (2.0 equiv), NaOH (2.0 equiv), EtOH (0.25 M), 23 °C, 16 h.

[0098] The utility of the (NHC)PdCl2(aniline) complex was evaluated in the Buchwald–Hartwig cross-coupling of aryl chlorides (Scheme 5). Thus, Pd–NHC catalysts bearing neutral aniline (6a) and 3-trifluoromethylaniline (6f) promoted the cross-coupling in excellent yields.

[0099] Scheme 5 [(IPr)PdCl2(aniline)]-Catalyzed Buchwald–Hartwig Cross-Coupling of Aryl Chlorides TIFF0007693229000045.tif29128

[0100] To gain insights into the properties of these novel (NHC)PdCl2(aniline) complexes, the HOMO and LUMO energy levels of representative (IPr)PdCl2(AN) (6a) were determined at the B3LYP 6-311++g(d,p) theoretical level (Figure 4). Computational evaluation of the ground-state properties based on the solid-phase structure determined by X-ray provides a powerful approach for predicting the reactivity of metal-NHC complexes. The determination of the HOMO (-6.08 eV) and LUMO (-1.76 eV) of (6a) indicates that the HOMO is located on palladium while the LUMO is located on the carbene ligand, chloride, and the leaving ligand. This can be compared with similar Pd-PEPPSI systems (-6.06 eV; -1.88 eV) and imidazolinylidene systems (7a) (-6.07 eV; -1.75 eV). To further understand the nature of the Pd-C(carbene) bond in the (NHC)PdCl2(aniline) complexes, the inventors performed NBO analysis. The Wiberg bond orders of the Pd-C(carbene) and Pd-N bonds in (6a) are 0.6776 and 0.3142 (Pd-C1, 0.6299; Pd-Cl2, 0.6305), which can be compared with similar [Pd(IPr)(3-Cl-py)Cl2] systems (Pd-C, 0.6871; Pd-N, 0.6302; Pd-Cl1, 0.6302; Pd-Cl2, 0.6278) and imidazolinylidene systems (7a) (Pd-C, 0.6745; Pd-N, 0.3024). The computational study suggests that the aniline ligand is sufficiently applicable to varying the electron density along the metal-NHC axis.

[0101] Scheme 6 IPr # -PEPPSI, [Pd(IPr # )(3-Cl-py)Cl2] General procedure for the synthesis of TIFF0007693229000046.tif39164 An oven-dried flask equipped with a stir bar was charged with IPr #HCl (552 mg, 0.44 mmol, 1.1 equiv), PdCl2 (71 mg, 0.4 mmol, 1.0 equiv), and K2CO3 (276 mg, 2.0 mmol, 5.0 equiv) were added, placed under positive argon pressure, and subjected to three degassing / refilling cycles under high vacuum. 3-Chloropyridine (2.0 mL) was added, and the reaction mixture was stirred at 80 °C for 24 h. After the indicated time, the reaction solution was cooled to room temperature, diluted with CH2Cl2, and filtered. The solution was collected and concentrated. The product was obtained as a white solid by trituration from CH2Cl2 / hexane. Yield 82% (494 mg). The structure of TIFF0007693229000047.tif49158 was determined by X-ray crystallographic analysis.

[0102] (Table 4) IPr in the cross-coupling reaction # -PEPPSI, [Pd(IPr # )(3-Cl-py)Cl2] activity The structure of TIFF0007693229000048.tif22987

[0103] The terms and expressions used herein are used as terms of description and not of limitation, and in using these terms and expressions there is no intention of excluding any equivalents or portions thereof of the features shown and described, and it will be recognized that various modifications are possible within the scope of the aspects of this application. Accordingly, although specific aspects and optional features are described in this application, it should be understood that those skilled in the art can rely on modifications and / or variations of the compositions, methods, and concepts disclosed herein, and that such modifications and variations are considered to be within the scope of the aspects of this application.

[0104] Numbered aspects The following exemplary aspects are presented, but the numbering should not be construed as indicating a level of importance.

[0105] Aspect 1 provides the following: A compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof: TIFF0007693229000049.tif53128 wherein, TIFF0007693229000050.tif2128 is a single bond or a double bond; R 1 and R 2 are each independently C 3~10 cycloalkyl, aryl, or heteroaryl, each of which is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl, and may be substituted with at least one group selected from the group consisting of; R 3 and R 4 are each independently hydrogen, optionally substituted C 3~10 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C 1~12 alkyl, or OC 1~12 alkyl, wherein any optional substitution is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C6~10 Aryl, and C 6~10 comprises at least one group selected from the group consisting of heteroaryl; or, R 3 and R 4 together with the ring to which they are attached, form C 4~20 cycloalkyl, C 6~20 aryl, or C 6~20 heteroaryl, and these are each halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl may be substituted with at least one group selected from the group consisting of; R 5 is H or C 1~3 alkyl; M is a transition metal; X is a counteranion; A is C 6~18 aryl or C 6~18 heteroaryl, and is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C6~10 Aryl, and C 6~10 optionally substituted with at least one group selected from the group consisting of heteroaryl; Each R is independently hydrogen or optionally substituted C 1~10 alkyl; m is 1, 2, or 3; n is 1, 2, 3, or 4.

[0106] Aspect 2 provides the following: The following structure: A compound of Aspect 1 having TIFF0007693229000051.tif50128, or a salt, solvate, geometric isomer, or stereoisomer thereof.

[0107] Aspect 3 provides the following: R 1 and R 2 are both aryl, a compound of any of Aspects 1-2.

[0108] Aspect 4 provides the following: Aryl is TIFF0007693229000052.tif28128, and wherein R 6 and R 7 are each independently C 1~12 alkyl, or C 1~12 alkyl substituted with at least one aryl; R 8 is hydrogen, or C 1~12 alkyl, or C 1~12 alkyl substituted with at least one aryl, a compound of any of Aspects 1-3.

[0109] Aspect 5 provides the following: R 8 is hydrogen, a compound of any of Aspects 1-4.

[0110] Aspect 6 provides the following: R6 and R 7 each is C 1~6 A compound of any one of Aspects 1 to 5, wherein each is alkyl.

[0111] Aspect 7 provides the following: R 6 and R 7 A compound of any one of Aspects 1 to 6, wherein each is C(H)(CH3)2.

[0112] Aspect 8 provides the following: A compound of any one of Aspects 1 to 7, wherein M is selected from the group consisting of Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, and Au.

[0113] Aspect 9 provides the following: A compound of any one of Aspects 1 to 8, wherein M is Pd.

[0114] Aspect 10 provides the following: A compound of any one of Aspects 1 to 9, wherein X is selected from the group consisting of F, Cl, Br, I, OSO2R, OSO3R, and OC(=O)R.

[0115] Aspect 11 provides the following: A compound of any one of Aspects 1 to 10, wherein the N-heterocyclic carbene (NHC) moiety of the compound of Formula I is selected from the group consisting of: In the formula of TIFF0007693229000053.tif65134, R 1 is selected from the group consisting of t-Bu, 1-adamantyl, cyclohexyl, i-Pr, methyl, ethyl, n-propyl, butyl, pentyl, and TIFF0007693229000054.tif22128; R 6 is CH(phenyl)2, CH(Me)2, CH(2-Np)2, or CH(Et)2; R 6' is CH(phenyl)2, CH(Me)2, or CH(Et); R8 is CH(phenyl)2, Me, OMe, or H.

[0116] Aspect 12 provides the following: The NHC moiety of the compound of formula I is selected from the group consisting of the following any compound of Aspects 1-11 consisting of TIFF0007693229000055.tif238157.

[0117] Aspect 13 provides the following: any compound of Aspects 1-12, wherein n is 2.

[0118] Aspect 14 provides the following: A is TIFF0007693229000056.tif12128, and wherein each R 9 is independently selected from the group consisting of OCH3, CF3, 2,6-dimethyl, 2,6-di-isopropyl, and hydrogen, and p is 0, 1, 2, 3, 4, or 5, any compound of Aspects 1-13.

[0119] Aspect 15 provides the following: R 5 is hydrogen or methyl, any compound of Aspects 1-14.

[0120] Aspect 16 provides the following: a step of contacting a compound having the following structure: TIFF0007693229000057.tif57128, or a salt, solvate, geometric isomer, or stereoisomer thereof, with a compound having the following structure: TIFF0007693229000058.tif14128, or a salt, solvate, geometric isomer, or stereoisomer thereof in a solvent, wherein each R 9independently, hydrogen, halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 alkyl, C 1~12 heteroalkyl, OC 1~12 alkyl, C 3~12 cycloalkyl, C 6~10 aryl, and C 6~10 heteroaryl selected from the group consisting of, step for preparing a compound of any of embodiments 1 to 15, comprising.

[0121] Embodiment 17 provides the following: The method of embodiment 16, wherein the solvent is a nonpolar aprotic solvent.

[0122] Embodiment 18 provides the following: The method of any of embodiments 16 to 17, wherein the solvent comprises chloroform, diethyl ether, deuterated chloroform, pentane, hexane, benzene, toluene, dichloromethane, or a mixture thereof.

[0123] Embodiment 19 provides the following: The method of any of embodiments 16 to 18, wherein the contact is carried out at room temperature.

[0124] Embodiment 20 provides the following: For forming a compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof, the following structure: A compound having TIFF0007693229000059.tif26128, or a salt, solvate, geometric isomer, or stereoisomer thereof, and A compound of formula MX2(A-N(H)(R 5 ))2, or a salt, solvate, geometric isomer, or stereoisomer thereof and A step of contacting in a solvent A method for preparing a compound according to any one of Embodiments 1 to 15, comprising:

[0125] Embodiment 21 provides the following: The method of Embodiment 20, wherein the contact is carried out in the presence of a base.

[0126] Embodiment 22 provides the following: The base is NaOC 1~4 alkyl, KOC 1~4 alkyl, lithium diisopropylamide, sodium hexamethyldisilazide, LiC 1~4 alkyl, or a combination thereof, in any one of the methods of Embodiments 20 to 21.

[0127] Embodiment 23 provides the following: The method of any one of Embodiments 20 to 22, wherein the solvent comprises a polar aprotic solvent.

[0128] Embodiment 24 provides the following: The method of any one of Embodiments 20 to 23, wherein the solvent comprises tetrahydrofuran, 2-N-methylpyrrolidone, dimethylformamide, acetonitrile, and combinations thereof.

[0129] Embodiment 25 provides the following: A compound of Formula II, or a salt, solvate, geometric isomer, or stereoisomer thereof: TIFF0007693229000060.tif37128 wherein R 5 is H or C 1~3 alkyl; R A , R 6 , and R 7 are independently optionally substituted C 1~12 alkyl, optionally substituted C 1~12 heteroalkyl, optionally substituted OC 1~12 alkyl, optionally substituted C 3~12 cycloalkyl, optionally substituted C 6~18Aryl, optionally substituted C 6~18 Heteroaryl, and C substituted with at least one aryl or heteroaryl 1~3 Selected from alkyl, where optional substitution is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 Alkyl, C 1~12 Heteroalkyl, OC 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, and C 6~10 Substitution by at least one group selected from the group consisting of heteroaryl; M is a transition metal; X is a counteranion; n is an integer from 1 to 4; Each R is independently hydrogen or optionally substituted C 1~10 Alkyl.

[0130] Aspect 26 provides the following: A compound of formula III, or a salt, solvate, geometric isomer, or stereoisomer thereof: TIFF0007693229000061.tif36128 wherein R 5 is H or optionally substituted C 1~3 Alkyl; R 6 、R 7 、and R 8 are independently optionally substituted C 1~12 Alkyl, optionally substituted C 1~12 Heteroalkyl, optionally substituted OC 1~12 Alkyl, optionally substituted C 3~12 Cycloalkyl, optionally substituted C 6~18Aryl, optionally substituted C 6~18 Heteroaryl, or C substituted with at least one aryl or heteroaryl 1~3 Selected from alkyl, where optional substitution is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 Alkyl, C 1~12 Heteroalkyl, OC 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, and C 6~10 Substitution by at least one group selected from the group consisting of heteroaryl; G is absent or optionally substituted C 1~12 Alkyl, optionally substituted C 1~12 Heteroalkyl, optionally substituted OC 1~12 Alkyl, optionally substituted C 3~12 Cycloalkyl, optionally substituted C 6~18 Aryl, optionally substituted C 6~18 Heteroaryl, or C substituted with at least one aryl or heteroaryl 1~3 Alkyl, where optional substitution is halogen, OR, SiR3, OSiR3, OSiR3, OSi(OR)3, BR3, BR2, B(OR)3, B(OR)2, CN, CF3, OCF3, SO2R, SO2N(R)2, SO3R, C(O)R, NR2, N(R)SO2R, N(R)SO2N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)C(O)OR, C 1~12 Alkyl, C 1~12 Heteroalkyl, OC 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10Substituted by at least one group selected from the group consisting of aryl and C 6~10 heteroaryl; M is a transition metal; X is a counteranion; Y is N or C; Z is N or C; n is an integer from 1 to 4; each R is independently hydrogen or optionally substituted C 1~10 alkyl, provided that both Y and Z are not C.

Claims

1. A compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof: wherein, is a single bond or a double bond; R 1 and R 2 are each independently ; R 3 and R 4 are each independently hydrogen, optionally substituted C 3～10 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C 1～12 alkyl, or OC 1～12 alkyl, where any substitution is halogen, OR, SiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 , (CH 2 ) 0～2 N(R)C(O)R, (CH 2 ) 0～2 N(R)N(R) 2 , N(R)C(O)OR, C 1～12 alkyl, C 1～12 heteroalkyl, OC 1～12 alkyl, C 3～12 cycloalkyl, C 6～10 aryl, and C 6～10 heteroaryl and contains at least 1 group selected from the group consisting of; or, R 3 and R 4 together with the ring to which they are attached, C 4～20 Cycloalkyl, C 6～20 Aryl, or C 6～20 Heteroaryl used to form, each of which is halogen, OR, SiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0～2 N(R)C(O)R, (CH 2 ) 0～2 N(R)N(R) 2 , N(R)C(O)OR, C 1～12 Alkyl, C 1～12 Heteroalkyl, OC 1～12 Alkyl, C 3～12 Cycloalkyl, C 6～10 Aryl, and C 6～10 Heteroaryl may be substituted with at least one group selected from the group consisting of; R 5 Is H or optionally substituted C 1～3 Alkyl; R6 and R7 are each independently C1-12 alkyl, or C1-12 alkyl substituted with at least one aryl; R8 is hydrogen, C1-12 alkyl, or C1-12 alkyl substituted with at least one aryl; M is Pd; X is a counter anion; A is halogen, OR, CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 and phenyl substituted with at least one group selected from the group consisting of N(R)C(O)OR; Each R is independently hydrogen or optionally substituted C 1～10 alkyl; m is 1, 2, or 3; n is 2. **Claim 2** The compound according to claim 1, or a salt, solvate, geometric isomer, or stereoisomer thereof, having the following structure: **Claim 3** R 8 being hydrogen, the compound according to claim 1. **Claim 4** R 6 and R 7 each being C 1～6 alkyl, the compound according to claim 1. **Claim 5** R 6 and R 7 each being C(H)(CH 3 ) 2 , the compound according to claim 1. **Claim 6** X being selected from the group consisting of F, Cl, Br, I, OSO 2 R, OSO 3 R, and OC(=O)R, the compound according to claim 1. **Claim 7** The compound according to claim 1, wherein the N-heterocyclic carbene (NHC) moiety of the compound of formula I is selected from the group consisting of: wherein R 1 is ; R 6 and R7 are CH(phenyl) 2 , CH(Me) 2 , CH(2-Np) 2 , or CH(Et) 2 ; R 8 is CH(phenyl) 2 , Me, or H.

8. The NHC moiety of the compound of formula I is selected from the group consisting of: The compound according to claim 1.

9. A is , wherein each R 9 is independently selected from the group consisting of OCH 3 and CF 3 , p is 1, 2, 3, 4, or 5, The compound according to claim 1.

10. R 5 is hydrogen or methyl, the compound according to claim 1.

11. The following structure: A compound having, or a salt, solvate, geometric isomer, or stereoisomer thereof, and the following structure: A compound having, or a salt, solvate, geometric isomer, or stereoisomer thereof are contacted in a solvent to form a compound of formula I, or a salt, solvate, geometric isomer, or stereoisomer thereof, wherein wherein each R 9 is independently halogen, OR, CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2and selected from the group consisting of N(R)C(O)OR, p is 1, 2, 3, 4, or 5, Step A method for preparing the compound according to claim 1, comprising

12. The method according to claim 11, wherein the solvent is a nonpolar aprotic solvent.

13. The method according to claim 12, wherein the solvent comprises chloroform, diethyl ether, deuterated chloroform, pentane, hexane, benzene, toluene, dichloromethane, or a mixture thereof.

14. The method according to claim 11, wherein the contact is carried out at room temperature.

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