TW201332975A - Bicyclic compounds as mPGES-1 inhibitors - Google Patents

Abstract

The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

Description

Bicyclic compound as mPGES-1 inhibitor [related application]

This application claims the Indian Provisional Application No. 372/MUM/2012, which was filed on February 9, 2012; the Indian Provisional Application No. 1302/MUM/2012, which was filed on April 24, 2012; and September 5, 2012 Japanese Provisional Application No. 2576/MUM/2012, which is filed in Japan; and US Provisional Application No. 61/602,227, filed on February 23, 2012; US Provisional Application No. 61/645,193, filed on May 10, 2012 And the benefit of U.S. Provisional Application Serial No. 61/707,838, filed on Sep. 28, 2012, which is hereby incorporated by reference in its entirety.

This application relates to bicyclic compounds which are useful as inhibitors of microsomal prostaglandin E synthetase-1 (mPGES-1).

There are many diseases or conditions that are inflammatory in nature. A major problem associated with existing treatments for inflammatory conditions is the lack of efficacy and/or side effects. Inflammatory diseases affecting the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation is also a common cause of pain.

Enzyme cyclooxygenase (COX) converts arachidonic acid into an unstable intermediate prostaglandin H ₂ (PGH ₂ ), which is further converted to other prostaglandins, including PGE ₂ , PGF _2α , PGD _2. Prostacyclin and thromboxane A ₂ . These arachidonic acid metabolites are known to have significant physiological and pathophysiological activities, including pro-inflammatory effects. COX enzymes exist in two forms, one constitutively expressed in many cells and tissues (COX-1), and the other in most cells and tissues induced by proinflammatory stimuli such as cytokines during an inflammatory response (COX) -2).

Among all prostaglandin metabolites, PGE _{2 is} particularly known as a potent proinflammatory mediator and is also known to induce fever and pain. Therefore, many drugs have been developed in view of inhibiting the formation of PGE ₂ , including "NSAID" (non-steroidal anti-inflammatory drugs) and "coxib" (selective COX-2 inhibitors). These drugs, primarily by inhibiting COX-1 and / or COX-2, thereby reducing the formation of PGE ₂ to function. However, inhibition of COX has disadvantages because it results in a decrease in the formation of all PGH ₂ metabolites, thereby reducing the beneficial properties of some metabolites. In view of this, it is suspected that a drug that acts by inhibiting COX causes an adverse biological effect. For example, non-selective inhibition of COX by NSAIDs can cause gastrointestinal side effects and affect platelet and renal function. Even though COX-2 is selectively inhibited by cox, although it reduces these gastrointestinal side effects, it can cause cardiovascular problems.

The combination of pharmacology, genetics, and neutralizing antibody methods demonstrates the importance of PGE ₂ in inflammation. Thus, the conversion of PGH ₂ to PGE ₂ by prostaglandin E synthetase (PGES) represents a critical step in the spread of inflammatory stimuli. Microsomal prostaglandin E synthetase-1 (mPGES-1) is an inducible PGES following exposure to pro-inflammatory stimuli. mPGES-1 is induced in the periphery and in the CNS by inflammation, and thus represents the target of acute and chronic inflammatory conditions. PGE ₂ is a major prostaglandin compound produced from arachidonic acid released by phospholipase (PLA), which drives the inflammatory process. Arachidonic acid is converted to the receptor PGH ₂ of mPGES-1 by the action of prostaglandin H synthetase (PGH synthase, cyclooxygenase), which is the end of PGH ₂ conversion into proinflammatory PGE ₂ Enzyme.

PGH ₂ can be converted to PGE ₂ by prostaglandin E synthetase (PGES). There are two microsomal prostaglandin E synthetases (mPGES-1 and mPGES-2) and one cytosolic prostaglandin E synthetase (cPGES). Therefore, an agent capable of inhibiting mPGES-1, and thus reducing the formation of a specific arachidonic acid metabolite PGE ₂ , is useful for treating inflammation. In addition, agents capable of inhibiting the action of proteins involved in the synthesis of leukotriene are also beneficial for the treatment of asthma and COPD.

Blocking PGE ₂ formation in animal models of inflammatory pain leads to inflammation, pain, and reduced fever response (Kojima et al, The Journal of Immunology 2008 , 180, 8361-6; Xu et al, The Journal of Pharmacology and Experimental Therapeutics 2008 , 326, 754-63). In abdominal aortic aneurysms, inflammation leads to degeneration of connective tissue and apoptosis of smooth muscle cells, which eventually leads to aortic dilatation and rupture. In animals lacking mPGES-1, disease progression and disease severity have been demonstrated to be slow (Wang et al, Circulation , 2008 , 117, 1302-1309).

Several lines of evidence indicate that PGE _{2 is} involved in malignant growth. PGE ₂ promotes tumor progression by stimulating cell proliferation and angiogenesis and by modulating immunosuppression. ₂ as a supportive role of PGE in the cancer, genetic deletion of mPGES-1 in mice inhibits tumor formation intestinal (Nakanishi et al., Cancer Research 2008, 68 (9 ), 3251-9). In humans, mPGES-1 is also upregulated in cancers such as colorectal cancer ( Schroder Journal of Lipid Research 2006 , 47, 1071-80).

Myositis is a chronic muscle disorder characterized by muscle weakness and fatigue. Proinflammatory cytokines and prostaglandins have been implicated in the development of myositis. In skeletal muscle tissue from patients with myositis, an increase in cyclooxygenase and mPGES-1 has been demonstrated, suggesting that mPGES-1 is the target for the treatment of this condition. ( Korotkova Annals of the Rheumatic Diseases 2008 , 67, 1596-1602).

In atherosclerosis, inflammation of the vascular structure leads to the formation of atheroma, which can eventually progress to infarction. In patients with carotid atherosclerosis, an increase in mPGES-1 has been reported in the plaque region (Gomez-Hernandez Atherosclerosis 2006 , 187, 139-49). In an animal model of atherosclerosis, mice lacking the mPGES-1 receptor were found to exhibit delayed atherogenesis and accompanied by a decrease in macrophage-derived foam cells and an increase in vascular smooth muscle cells (Wang, Proceedings of National Academy of Sciences 2006 , 103(39), 14507-12).

International Publication No. WO 2006/063466, WO 2007/059610, WO 2010/034796, WO 2010/100249, WO 2012/055995, and WO 2012/110860 disclose numerous statements as microsomes A heterocyclic compound of an inhibitor of prostaglandin E synthetase-1 (mPGES-1).

This application relates to compounds which may be inhibitors of the mPGES-1 enzyme and which will therefore be suitable for the treatment of pain and inflammation in a variety of diseases or conditions.

In one aspect, the invention relates to a compound of formula (I):

Or a pharmaceutically acceptable salt thereof, wherein Y is a bond or is selected from the group consisting of NR ^c , O and CR ^c R ^d ; A is selected from the group consisting of C _6-14 aryl, 5-14 membered heteroaryl and 3-15 members a heterocyclic group; the same or different Z ¹ , Z ² and Z ^{3 are} independently selected from N and CR ² ; the limitation is that Z ¹ , Z ² and Z ^{3 are} not N at the same time; G ¹ may be the same or different , G ² and G ^{3 are} independently selected from N and CR ³ ; the constraint is that G ¹ , G ² and G ^{3 are} not N at the same time; another limiting condition is Z ¹ , Z ² , Z ³ , G ¹ , At least one of G ² and G ³ is N; L is a bond or is selected from (CR ^x R ^y ) _n NR ^x , (CR ^x R ^y ) _n C(O)NR ^x , (CR ^x R ^y ) _n C (O)O, (CR ^x R ^y ) _n NR ^x C(O), (CR ^x R ^y ) _n NR ^x C(O)NR ^y , (CR ^x R ^y ) _n NR ^x C(O)O, (CR ^x R ^y ) _n NR ^x SO ₂ , (CR ^x R ^y ) _n OC(O), (CR ^x R ^y ) _n OC(O)O, (CR ^x R ^y ) _n OC(O)NR ^x , (CR ^x R ^y ) _n S(O), (CR ^x R ^y ) _n SO ₂ , (CR ^x R ^y ) _n S(O)NR ^x , (CR ^x R ^y ) _n SO ₂ NR ^x and ( CR ^x R ^y ) _n S; W is selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-10 alkenyl, substituted or unsubstituted C _2-10 alkynyl, substituted or unsubstituted And a C _1-8 alkoxy C _1-8 alkyl group, a substituted or unsubstituted halogen C _1-8 alkyl group, a substituted or unsubstituted hydroxy C _1-8 alkyl group, substituted or not Substituted C _3-12 cycloalkyl, substituted or unsubstituted C _3-8 cycloalkenyl, substituted or unsubstituted C _6-14 aryl, substituted or unsubstituted 3 to 15 a heterocyclic group and a substituted or unsubstituted 5 to 14 membered heteroaryl; R ¹ is selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _{2 -10} alkenyl, substituted or unsubstituted C _2-10 alkynyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or unsubstituted halogen C _{1 -8} alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl, substituted or unsubstituted C _3-8 cycloalkenyl, substituted or unsubstituted C _3-8 cycloalkenyl C _1-8 alkyl, substituted or unsubstituted C _6-14 aryl group, a substituted or non-substituted C _6-14 aryl C _1-8 alkyl group, a substituted or non-substituted 3-15 membered heterocyclyl, substituted or non- Instead 3-15 membered heterocyclyl C _1-8 alkyl group, a substituted or unsubstituted aryl group of 5-14 membered heteroaryl and substituted or unsubstituted aryl group of 5-14 membered heteroaryl C _1-8 alkyl R ² and R ³ which may be the same or different are each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted Or unsubstituted C _2-10 alkenyl, substituted or unsubstituted C _2-10 alkynyl, substituted or unsubstituted C _1-8 alkoxy, substituted or unsubstituted C _{1 -8} alkoxy C _1-8 alkyl, substituted or unsubstituted halo C _1-8 alkyl, substituted or unsubstituted halo C _1-8 alkoxy, substituted or unsubstituted Hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl, substituted or unsubstituted C _3-8 cycloalkenyl, substituted or unsubstituted C _3-8 cycloalkenyl C _1-8 alkyl, substituted or unsubstituted C _6-14 aryl, substituted or unsubstituted the C _6-14 aryloxy, substituted or non-substituted C _6-14 aryl C _1-8 alkyl, substituted or non-substituted 3-15 membered heterocyclyl, A substituted or unsubstituted 3-15 membered heterocyclyl of C _1-8 alkyl group, a substituted or unsubstituted aryl of 5-14 membered heteroaryl group, a substituted or unsubstituted aryl group of 5-14 membered heteroaryl C _1-8 alkyl, -C(O)R ^a , -C(O)NR ^a R ^b , -C(O)OR ^a , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -N(R ^a )SO ₂ R ^b , -OC(O)R ^a , -OC(O)OR ^a , -OC( O) NR ^a R ^b , -S(O)R ^a , -SO ₂ R ^a , -S(O)NR ^a R ^b , -SO ₂ NR ^a R ^b and -SR ^a ; R ⁴ at each occurrence All independently selected from halogen, nitro, cyano, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-10 alkenyl, substituted or unsubstituted C _2-10 alkynyl, substituted or unsubstituted C _1-8 alkoxy, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or unsubstituted Halogen C _1-8 alkyl, substituted or unsubstituted halogen C _1-8 alkoxy, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 Cycloalkyl, substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl, substituted or unsubstituted C _3-8 cycloalkenyl, substituted or not Substituted C _3-8 cycloalkenyl C _1-8 alkyl, substituted or unsubstituted C _6-14 aryl, C _6-14 aryloxy, substituted or unsubstituted C _{6- 14} aryl C _1-8 alkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclyl C _1-8 alkyl, substituted or unsubstituted Substituted 5-14 membered heteroaryl, substituted or unsubstituted 5-14 membered heteroaryl C _1-8 alkyl; -C(O)R ^a , -C(O)NR ^a R ^b , -C(O)OR ^a , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -N(R ^a ) SO ₂ R ^b , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^a R ^b , -S(O)R ^a , -SO ₂ R ^a , -S( O) NR ^a R ^b , -SO ₂ NR ^a R ^b and -SR ^a ; each occurrence, the same or different R ^a and R ^{b are} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or unsubstituted halogen C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl, substituted or unsubstituted C _{6- 14} aryl, substituted or unsubstituted C _6-14 aryl C _1-8 alkyl, substituted or unsubstituted 3-15 membered heterocyclic group, substituted or unsubstituted 3-15 member Heterocyclyl C _1-8 alkyl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted 5-14 membered heteroaryl C _1-8 alkyl; or R ^a and R ^b together with the atom to which it is attached forms a substituted or unsubstituted ring and wherein the ring optionally contains one or more heteroatoms selected from O, N or S; in each occurrence, may be the same or different R ^c and R ^{d are each} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or Unsubstituted halogen C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl, substituted or unsubstituted C _6-14 aryl, substituted or unsubstituted C _6-14 aryl C _1-8 alkyl, substituted or non-substituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclyl of C _1-8 alkyl, substituted or unsubstituted The substituted 5-14 membered heteroaryl, and substituted or unsubstituted aryl of 5-14 membered heteroaryl C _1-8 alkyl group; or when Y is CR ^c R ^d, R ^c and R ^d together they are attached The "C" atoms together form a substituted or unsubstituted ring and wherein the ring optionally contains one or more heteroatoms selected from O, N or S; or, when Y is NR ^c , R ^c and R ¹ Together with the "N" atom to which it is attached, a substituted or unsubstituted ring is formed and wherein the ring optionally contains another heteroatom selected from O, N or S; each occurrence may be the same or different R ^X and R ^{y are each} independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or not Substituted halogen C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _{3 -8} cycloalkyl C _1-8 alkyl, substituted or unsubstituted C _6-14 aryl, substituted or unsubstituted C _6-14 aryl C _1-8 alkyl, substituted or not the substituted 3-15 membered heterocyclyl, substituted or unsubstituted 3-15 membered heterocyclyl of C _1-8 alkyl A substituted or unsubstituted aryl group of 5-14 membered heteroaryl and substituted or unsubstituted aryl group of 5-14 membered heteroaryl C _1-8 alkyl; or R ^x and R ^y taken together with the atoms to which they are attached a substituted or unsubstituted ring wherein the ring optionally contains one or more heteroatoms selected from O, N or S; "m" is an integer in the range of 0 to 4, including both 0 and 4; And "n" is an integer ranging from 0 to 6, including both 0 and 6.

Compounds of formula (I) may relate to one or more embodiments. Examples of formula (I) include compounds of formula (II) and compounds of formula (III) as described below. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention to the specific embodiments. It should also be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment as defined herein. Accordingly, the present invention encompasses all possible combinations and permutations of various independently described embodiments. For example, the invention provides a compound of formula (I), as defined above, wherein Y is O (according to one of the following definitions), R ² is hydrogen, C _1-4 alkyl or halo C _1-8 alkyl ( Another embodiment according to the definition below) and R ³ is hydrogen or C _1-4 alkyl.

According to one embodiment, a compound of formula (I) is specified, wherein at least one of Z ¹ , Z ² and Z ³ is CR ² .

According to another embodiment, a compound of formula (I) is specified, wherein at least one of Z ¹ , Z ² and Z ³ is N.

According to another embodiment, a compound of formula (I) is specified, wherein Z ¹ is N or CR ² , Z ² is CR ² and Z ³ is N or CR ² .

According to another embodiment, a compound of formula (I) is specified, wherein G ¹ is N or CR ³ and G ² and G ³ are CR ³ .

According to another embodiment, there is provided specifically a compound of formula (I), wherein Z ¹ is N or CR ² , Z ² is CR ² , Z ³ is N or CR ² , G ¹ is N or CR ³ , and G ² and G ³ is CR ³ ; the constraint is that at least one of Z ¹ , Z ² , Z ³ , G ¹ , G ² and G ³ is N.

According to another embodiment, there is provided specifically provided a compound of formula (I), wherein each occurrence of R ² is independently hydrogen, C _1-4 alkyl (eg methyl, ethyl or tert-butyl) or halogen C _1-8 alkyl (e.g., trifluoromethyl).

According to another embodiment, a compound of formula (I) is specifically provided wherein R ² is independently hydrogen, methyl or trifluoromethyl at each occurrence.

According to another embodiment, there is provided specifically provided a compound of formula (I), wherein each occurrence of R ³ is independently hydrogen or C _1-4 alkyl (eg methyl, ethyl or tert-butyl).

According to another embodiment, the compound of formula to provide a specific (the I), wherein R ³ are at each occurrence is independently hydrogen or methyl.

According to another embodiment, a compound of formula (I) is specifically provided wherein Z ¹ is N, Z ² is CR ² , Z ³ is N, and G ¹ , G ² and G ³ are CR ³ . In this embodiment, R ² is independently hydrogen, methyl or trifluoromethyl at each occurrence and R ³ is independently hydrogen or methyl at each occurrence.

According to another embodiment, a compound of formula (I) is specified, wherein Z ¹ is N, Z ² and Z ³ are CR ² , and G ¹ , G ² and G ³ are CR ³ . In this embodiment, R ² is independently hydrogen, methyl or trifluoromethyl at each occurrence and R ³ is independently hydrogen or methyl at each occurrence.

According to another embodiment, a compound of formula (I) is specifically provided wherein Z ¹ and Z ² are CR ² , Z ³ is N, and G ¹ , G ² and G ³ are CR ³ . In this embodiment, R ² is independently hydrogen, methyl or trifluoromethyl at each occurrence and R ³ is independently hydrogen or methyl at each occurrence.

According to another embodiment, a compound of formula (I) is specifically provided wherein Z ¹ , Z ² and Z ³ are CH, and G ¹ is N, and G ² and G ³ are CH.

According to another embodiment, a compound of formula (I) is specified, wherein Y is O.

According to another embodiment, a compound of formula (I) is specified, wherein Y is NR ^c . In this embodiment, R ^c is hydrogen, C _1-4 alkyl (eg methyl or ethyl) or R ^c and R ¹ together with the N to which they are attached form a morpholine ring.

According to another embodiment, a compound of formula (I) is specified, wherein Y is NH.

According to a further embodiment, there is provided in particular a compound of formula (I), wherein R ¹ is substituted or unsubstituted C _1-8 alkyl, preferably unsubstituted C _1-8 alkyl, and more preferably Unsubstituted C _1-4 alkyl (eg methyl, ethyl, isopropyl or tert-butyl).

According to another embodiment, the compound of formula to provide a specific (the I), wherein R ¹ is methyl, ethyl, isopropyl or tert-butyl.

According to another embodiment, there is provided specifically a compound of formula (I), wherein R ¹ is substituted or unsubstituted halo C _1-8 alkyl, preferably unsubstituted halo C _1-8 alkyl (eg 2 , 2,2-trifluoroethyl).

According to another embodiment, the compound of formula to provide a specific (the I), wherein R ¹ is 2,2,2-trifluoroethyl.

According to another embodiment, there is provided specifically a compound of formula (I), wherein R ¹ is substituted or unsubstituted C _6-14 aryl, preferably substituted or unsubstituted phenyl, and more preferably Substituted phenyl. In this embodiment, the C _6-14 aryl group or the substituent on the phenyl group may be one or more and independently selected from halogen (for example, F, Cl or Br), C _1-4 alkyl (for example, methyl group). Or ethyl) and a halogen C _1-8 alkyl group (e.g., trifluoromethyl).

According to another embodiment, there is provided specifically provided a compound of formula (I), wherein R ¹ is optionally selected from one or more of halogen (eg, F, Cl or Br), C _1-4 alkyl (eg methyl or A phenyl group substituted with a substituent of an ethyl group and a halogen C _1-8 alkyl group (for example, a trifluoromethyl group). In a preferred embodiment, the phenyl group in R ¹ has a substituent at the 3 position and optionally one or more other positions.

According to another embodiment, the compound of formula to provide a specific (the I), wherein R ¹ is substituted phenyl and the substituents are independently selected from fluoro, methyl and trifluoromethyl.

According to another embodiment, there is provided specifically a compound of formula (I), wherein R ¹ is substituted or unsubstituted C _3-12 cycloalkyl, preferably substituted or unsubstituted C _3-6 cycloalkyl More preferably, it is a substituted or unsubstituted cyclohexyl group. In this embodiment, the substituent on the C _3-12 cycloalkyl group, the C _3-6 cycloalkyl group or the cyclohexyl group may be one or more and independently selected from halogen (for example, F, Cl or Br), C. _1-4 alkyl (e.g., methyl) and halogen _C1-8 alkyl (e.g., trifluoromethyl).

According to a further embodiment, there is provided in particular a compound of formula (I), wherein R ¹ is optionally selected from halogen (for example F, Cl or Br), C _1-4 alkyl (for example methyl), by one or more And a cyclohexyl group substituted with a substituent of a halogen C _1-8 alkyl group (for example, a trifluoromethyl group).

According to another embodiment, the compound of formula to provide a specific (the I), wherein R ¹ is the cyclohexyl group substituted by one or more substituents and are independently selected fluoro, methyl and trifluoromethyl.

According to a further embodiment, there is provided in particular a compound of formula (I), wherein R ¹ is substituted or unsubstituted 5-14 membered heteroaryl, preferably substituted or unsubstituted pyridine, and more preferably Substituted pyridine. In this embodiment, the substituent on the pyridine ring may be one or more and independently selected from halogen (e.g., F, Cl or Br), C _1-4 alkyl (e.g., methyl, ethyl), and halogen C. _1-8 alkyl (e.g., trifluoromethyl).

According to a further embodiment, there is provided in particular a compound of formula (I), wherein R ¹ is optionally selected from halogen (for example F, Cl or Br), C _1-4 alkyl (for example methyl), by one or more And a pyridine substituted with a substituent of a halogen C _1-8 alkyl group (for example, a trifluoromethyl group).

According to another embodiment, the compound of formula to provide a specific (the I), wherein R ¹ is substituted pyridyl and substituted with one or more of the group is trifluoromethyl.

According to another embodiment, there is provided specifically a compound of formula (I), wherein R ¹ is methyl, ethyl, isopropyl, tert-butyl, 2,2,2-trifluoroethyl, 3-(trifluoromethyl) Phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro- 4-(Trifluoromethyl)phenyl, 6-(trifluoromethyl)pyridin-3-yl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl) Base) cyclohexyl, (1 s , 4 s ) -4-(trifluoromethyl)cyclohexyl or (1 r , 4 r )-4-(trifluoromethyl)cyclohexyl.

According to another embodiment, a compound of formula (I), wherein A is a C _6-14 aryl group, preferably a phenyl group, is specifically provided.

According to another embodiment, a compound of formula (I) is specified, wherein A is a 5-14 membered heteroaryl group, preferably pyridine.

According to a further embodiment, there is provided in particular a compound of formula (I), wherein each occurrence of R ⁴ is independently halogen (for example F, Cl or Br), C _1-4 alkyl (for example methyl, ethyl). Halogen C _1-8 alkyl (eg difluoromethyl) or C _1-8 alkoxy (eg methoxy).

According to another embodiment, there is provided specifically provided a compound of formula (I), wherein each occurrence of R ⁴ is independently OCH ₃ , CH ₃ , CHF ₂ , Cl or F.

According to another embodiment, a compound of formula (I) is specified, wherein m is 0, 1 or 2.

According to another embodiment, there is provided specifically provided a compound of formula (I), wherein each occurrence of R ⁴ is independently OCH ₃ , CH ₃ , Cl or F and m is 1 or 2.

According to another embodiment, a compound of formula (I) is specified, wherein L is (CR ^x R ^y ) _n NR ^x C(O).

According to another embodiment, there is provided specifically provided a compound of formula (I), wherein R ^x and R ^{y are} independently selected from hydrogen and C _1-8 alkyl (eg methyl).

According to another embodiment, a compound of formula (I) is specified, wherein L is (CR ^x R ^y ) _n NR ^x C(O). In this embodiment, R ^x and R ^y are each independently selected from hydrogen and C _1-4 alkyl (eg, methyl), and n is 1 or 2.

According to another embodiment, a compound of formula (I) is specified, wherein L is CH ₂ NHC(O).

According to another embodiment, there is provided specifically a compound of formula (I), wherein W is substituted or unsubstituted C _1-8 alkyl (eg methyl, ethyl, isopropyl or tert-butyl), halogen C _1-8 alkyl (eg 1-fluoro-2-methylpropan-2-yl), hydroxy C _1-8 alkyl (eg 1-hydroxy-2-methylpropan-2-yl), tetrahydrofuranyl or S )-tetrahydrofuran-2-yl.

According to another embodiment, there is provided specifically a compound of formula (I) wherein W is isopropyl, tert-butyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan- 2-Based, tetrahydrofuranyl or ( S )-tetrahydrofuran-2-yl.

According to another embodiment, a compound of formula (I) is specifically provided wherein L is a bond and W is hydrogen.

According to another embodiment, there is provided specifically a compound of formula (I) wherein L is CH ₂ NHC(O) and W is isopropyl, tert-butyl, 1-fluoro-2-methylpropan-2-yl, 1 - hydroxy-2-methylpropan-2-yl, tetrahydrofuranyl or ( S )-tetrahydrofuran-2-yl.

According to one embodiment, the compound of formula to provide a specific (the I), on which the value of IC mPGES _1-50 activity of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM.

The following description of the compounds of formula (II) and formula (III) and the groups Y, A, Z ¹ , Z ² , Z ³ , G ¹ , G ² , G ³ , L, W, R ¹ , R ² , R ³ Other embodiments relating to R ⁴ , R ^a , R ^b , R ^c , R ^d , R ^x , R ^y , "m" and "n" (and groups defined therein). It will be appreciated that these examples are not limited to use in conjunction with formula (II) or formula (III), but are independently and individually applicable to the compound of formula (I). For example, in one embodiment described below, the invention specifically provides a compound of formula (II) or formula (III) wherein R ³ is hydrogen or methyl and thus also provides a compound of formula (I), wherein R ³ It is hydrogen or methyl.

The invention also provides a compound of formula (II) which is an example of a compound of formula (I).

The invention therefore provides a compound of formula (II):

Or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^c ; Z ¹ and Z ³ which may be the same or different are independently selected from N and CR ² ; G ¹ is selected from N and CR ³ ; The restriction condition is that at least one of Z ¹ , Z ³ and G ¹ is N; the same or different Q ¹ , Q ² , Q ³ and Q ^{4 are} independently selected from N, CH and CR ⁴ ; Q ² , Q ³ and Q ^{4 are} not simultaneously N; W is selected from substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkane a substituted, unsubstituted, halo C _1-8 alkyl group, a substituted or unsubstituted hydroxy C _1-8 alkyl group, a substituted or unsubstituted C _3-12 cycloalkyl group, and substituted or Unsubstituted tetrahydrofuryl/tetrahydrofuranyl; R ¹ is selected from substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkane a substituted, unsubstituted, halo C _1-8 alkyl group, a substituted or unsubstituted hydroxy C _1-8 alkyl group, a substituted or unsubstituted C _3-12 cycloalkyl group, substituted or the unsubstituted C _6-14 aryl group, a substituted or unsubstituted heterocyclic group, and the 3-15 membered substituted or unsubstituted The substituted 5-14 membered heteroaryl; may be the same or different from R ² and R ³ are at each occurrence is independently selected from hydrogen, halo, nitro, cyano, hydroxyl, substituted or non-substituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy, substituted or unsubstituted halogen C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl a substituted or unsubstituted C _3-12 cycloalkyl group and a substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl group; at each occurrence, R ^{4 is} independently selected from Halogen, nitro, cyano, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy, substituted or unsubstituted C _1-8 Alkoxy C _1-8 alkyl, substituted or unsubstituted halo C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _{3 - 12} cycloalkyl and substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl; at each occurrence, R ^{c is} independently selected from substituted or unsubstituted C _1-8 An alkyl group and a substituted or unsubstituted C _6-14 aryl C _1-8 alkyl group; or R ^c and R ¹ together with the N to which they are attached Forming a morpholine ring; the same or different R ^x and R ^y are each independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, and substituted or unsubstituted C _{6 -14} aryl C _1-8 alkyl; and "n" is an integer in the range of 1 to 4, including both 1 and 4.

Compounds of formula (II) may relate to one or more embodiments. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention to the specific embodiments. It should also be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment as defined herein. Accordingly, the present invention encompasses all possible combinations and permutations of various independently described embodiments. For example, the invention provides a compound of formula (II) as defined above, wherein Y is NH (according to one of the following definitions) and n is 1 (another embodiment according to the definition below).

According to one embodiment, a compound of formula (II) is specifically provided wherein Y is NH.

According to another embodiment, a compound of formula (II) is specified, wherein Y is O.

According to another embodiment, a compound of formula (II) is specified, wherein Y is NR ^c . In this embodiment, R ^c is C _1-4 alkyl (eg methyl or ethyl) or R ^c and R ¹ together with the N to which they are attached form a morpholine ring.

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ is N, Z ³ is CR ² and G ¹ is CR ³ .

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ and Z ³ are N and G ¹ is CR ³ .

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ is CR ² , Z ³ is N and G ¹ is CR ³ .

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ and Z ³ are CR ² and G ¹ is N.

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein each occurrence of R ² is independently hydrogen, C _1-4 alkyl (eg methyl, ethyl or tert-butyl) or halogen C _1-8 alkyl (e.g., trifluoromethyl).

According to another embodiment, a compound of formula (II) is specifically provided wherein R ² is independently hydrogen, methyl or trifluoromethyl at each occurrence.

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein each occurrence of R ³ is independently hydrogen or C _1-4 alkyl (eg methyl, ethyl or tert-butyl).

According to another embodiment, the compound of formula to provide a specific (II), wherein R ³ are at each occurrence is independently hydrogen or methyl.

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ is N, Z ³ is CH and G ¹ is CH.

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ and Z ³ are N and G ¹ is CH.

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ is CH, Z ³ is N and G ¹ is CH.

According to another embodiment, a compound of formula (II) is specifically provided wherein Z ¹ and Z ³ are CH and G ¹ is N.

According to another embodiment, the compound of formula to provide a specific (II), wherein R ¹ is a substituted or unsubstituted alkyl group of C _1-8, preferably non-substituted C _1-8 alkyl, more preferably not Substituted C _1-4 alkyl (e.g., methyl, ethyl, isopropyl or tert-butyl).

According to another embodiment, the compound of formula to provide a specific (II), wherein R ¹ is methyl, ethyl, isopropyl or tert-butyl.

According to another embodiment, there is provided specifically a compound of formula (II), wherein R ¹ is substituted or unsubstituted halo C _1-8 alkyl, preferably unsubstituted halo C _1-8 alkyl (eg 2 , 2,2-trifluoroethyl).

According to another embodiment, the compound of formula to provide a specific (II), wherein R ¹ is 2,2,2-trifluoroethyl.

According to another embodiment, there is provided specifically a compound of formula (II), wherein R ¹ is substituted or unsubstituted C _6-14 aryl, preferably substituted or unsubstituted phenyl, and more preferably Substituted phenyl. In this embodiment, the C _6-14 aryl group or the substituent on the phenyl group may be one or more and independently selected from halogen (for example, F, Cl or Br), C _1-4 alkyl (for example, methyl group). , ethyl) and halogen C _1-8 alkyl (eg trifluoromethyl).

According to a further embodiment, there is provided in particular a compound of formula (II), wherein R ¹ is optionally selected from one or more of halogen (eg F, Cl or Br), C _1-4 alkyl (eg methyl, A phenyl group substituted with a substituent of an ethyl group and a halogen C _1-8 alkyl group (for example, a trifluoromethyl group).

According to another embodiment, the compound of formula to provide a specific (II), wherein R ¹ is the phenyl group and a substituted or more substituents independently selected from fluoro, methyl and trifluoromethyl.

According to another embodiment, there is provided specifically a compound of formula (II), wherein R ¹ is substituted or unsubstituted C _3-12 cycloalkyl, preferably substituted or unsubstituted C _3-6 cycloalkyl More preferably, it is a substituted or unsubstituted cyclohexyl group. In this embodiment, the substituent on the C _3-12 cycloalkyl group, the C _3-6 cycloalkyl group or the cyclohexyl group may be one or more and independently selected from halogen (for example, F, Cl or Br), C. _1-4 alkyl (e.g., methyl) and halogen _C1-8 alkyl (e.g., trifluoromethyl).

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein R ¹ is optionally selected from halogen (eg, F, Cl or Br), C _1-4 alkyl (eg methyl), by one or more And a cyclohexyl group substituted with a substituent of a halogen C _1-8 alkyl group (for example, a trifluoromethyl group).

According to another embodiment, the compound of formula to provide a specific (II), wherein R ¹ is the cyclohexyl group substituted by one or more substituents and are independently selected fluoro, methyl and trifluoromethyl.

According to a further embodiment, there is provided in particular a compound of formula (II), wherein R ¹ is substituted or unsubstituted 5-14 membered heteroaryl, preferably substituted or unsubstituted pyridine, more preferably substituted Pyridine. In this embodiment, the substituent on the pyridine may be one or more and independently selected from halogen (for example, F, Cl or Br), C _1-4 alkyl (for example methyl or ethyl) and halogen C _{1 . -8} alkyl (e.g., trifluoromethyl).

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein R ¹ is optionally selected from halogen (eg, F, Cl or Br), C _1-4 alkyl (eg methyl), by one or more And a pyridine substituted with a substituent of a halogen C _1-8 alkyl group (for example, a trifluoromethyl group).

According to another embodiment, the compound of formula to provide a specific (II), wherein R ¹ is pyridyl and substituted with one or more of the substituents is trifluoromethyl.

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein R ¹ is methyl, ethyl, isopropyl, tert-butyl, 2,2,2-trifluoroethyl, 3-(trifluoromethyl) Phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro- 4-(Trifluoromethyl)phenyl, 6-(trifluoromethyl)pyridin-3-yl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl) Base) cyclohexyl, (1 s , 4 s ) -4-(trifluoromethyl)cyclohexyl or (1 r , 4 r )-4-(trifluoromethyl)cyclohexyl.

According to another embodiment, a compound of formula (II) is specified, wherein n is 1.

According to another embodiment, a compound of formula (II) is specified, wherein R ^x is hydrogen.

According to another embodiment, a compound of formula (II) is specified, wherein R ^y is hydrogen.

According to another embodiment, a compound of formula (II) is specified, wherein Q ¹ is N.

According to another embodiment, the compound of formula to provide a specific (II), wherein Q ¹ is CH or CR ^4.

According to another embodiment, a compound of formula (II) is specified, wherein Q ² is CH or CR ⁴ .

According to another embodiment, the compound of formula to provide a specific (II), wherein Q ³ is N or CH.

According to another embodiment, a compound of formula (II) is specified, wherein Q ⁴ is CH or CR ⁴ .

According to another embodiment, a compound of formula (II) is specifically provided wherein Q ¹ is N, CH or CR ⁴ , Q ² is CH or CR ⁴ , Q ³ is N or CH, and Q ⁴ is CR ⁴ .

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein each occurrence of R ⁴ is independently halogen (eg, F, Cl or Br), C _1-4 alkyl (eg methyl or ethyl). Halogen C _1-8 alkyl (eg difluoromethyl) or C _1-8 alkoxy (eg methoxy).

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein each occurrence of R ⁴ is independently OCH ₃ , CH ₃ , CHF ₂ , Cl or F.

According to another embodiment, a compound of formula (II) is specifically provided wherein Q ¹ is N, CH or CR ⁴ , Q ² is CH or CR ⁴ , Q ³ is N or CH, and Q ⁴ is CR ⁴ . In this embodiment, R ⁴ is OCH ₃ , CH ₃ , CHF ₂ , Cl or F.

According to another embodiment, there is provided specifically provided a compound of formula (II), wherein W is substituted or unsubstituted C _1-8 alkyl (eg methyl, ethyl, isopropyl or tert-butyl), halogen C _1-8 alkyl (eg 1-fluoro-2-methylpropan-2-yl), hydroxy C _1-8 alkyl (eg 1-hydroxy-2-methylpropan-2-yl), tetrahydrofuranyl or S )-tetrahydrofuran-2-yl.

According to another embodiment, there is provided specifically a compound of formula (II) wherein W is isopropyl, tert-butyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan- 2-Based, tetrahydrofuranyl or ( S )-tetrahydrofuran-2-yl.

According to one embodiment, the compound of formula to provide a specific (II), on which the value of IC mPGES _1-50 activity of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM.

The following description of the compound of formula (III) and the groups R ¹ , R ² , R ³ , Y, Z ¹ , Z ³ , G ¹ , Q ¹ , Q ² , Q ³ , Q ⁴ , W, n, R ^x and Other embodiments related to R ^y (and the groups defined therein). It will be appreciated that these examples are not limited to use in conjunction with formula (III), but are independently and individually applicable to the compounds of formula (I) and formula (II). For example, in one embodiment described below, the invention specifically provides a compound of formula (III) wherein Y is NH and thus also provides a compound of formula (I) or formula (II) wherein Y is NH.

The invention also provides a compound of formula (III) which is an example of a compound of formula (I).

The invention therefore provides a compound of formula (III):

Or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of NH and O; and Z ¹ and Z ³ which may be the same or different are independently selected from N and CR ² ; the limitation is at least Z ¹ and Z ³ One is N; the same or different Q ¹ , Q ² , Q ³ and Q ^{4 are} independently selected from N, CH and CR ⁴ ; the limitation is that Q ² , Q ³ and Q ^{4 are} not N at the same time; Or a substituted or unsubstituted C _1-8 alkyl group, a substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl group, a substituted or unsubstituted halogen C _1-8 An alkyl group, a substituted or unsubstituted hydroxy C _1-8 alkyl group, a substituted or unsubstituted C _3-12 cycloalkyl group, and a substituted or unsubstituted tetrahydrofuranyl group; R ¹ is selected from substituted Or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or unsubstituted halogen C _1-8 alkyl, substituted Or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _6-14 aryl, substituted or unsubstituted 3 -15 membered heterocyclic group and substituted or unsubstituted 5-14 membered heteroaryl; the same or different R ² and R ³ each time When present, are independently selected from the group consisting of hydrogen, halogen, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy, and substituted or unsubstituted halide. C _1-8 alkyl; and at each occurrence, R ^{4 is} independently selected from halo, nitro, cyano, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted Substituted C _1-8 alkoxy, substituted or unsubstituted halo C _1-8 alkyl and substituted or unsubstituted C _3-12 cycloalkyl.

Compounds of formula (III) may relate to one or more embodiments. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention to the specific embodiments. It should also be understood that the embodiments defined herein may be used independently or in conjunction with any definition or any other embodiment as defined herein. Accordingly, the present invention encompasses all possible combinations and permutations of various independently described embodiments. For example, the invention provides a compound of formula (III), as defined above, wherein R ² is hydrogen, methyl or trifluoromethyl (according to one of the following definitions) and R ³ is hydrogen or methyl (based on Another embodiment).

According to one embodiment, a compound of formula (III) is specifically provided wherein Y is NH.

According to another embodiment, a compound of formula (III) is specified, wherein Y is O.

According to another embodiment, a compound of formula (III) is specified, wherein Z ¹ is N and Z ³ is CR ² .

According to another embodiment, a compound of formula (III) is specified, wherein Z ¹ and Z ³ are N.

According to another embodiment, a compound of formula (III) is specified, wherein Z ¹ is CR ² and Z ³ is N.

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein each occurrence of R ² is independently hydrogen, C _1-4 alkyl (eg methyl, ethyl, tert-butyl) or halogen C _1-8 alkyl (e.g., trifluoromethyl).

According to another embodiment, a compound of formula (III) is specifically provided wherein R ² is independently hydrogen, methyl or trifluoromethyl at each occurrence.

According to another embodiment, a compound of formula (III) is specified, wherein Z ¹ is N and Z ³ is CH or N.

According to another embodiment, the compound of formula to provide a particular (III), wherein Z ¹ is CH and Z ³ is N.

According to another embodiment, (III) provides a compound of a specific formula, wherein R ³ at each occurrence are independently hydrogen or C _1-4 alkyl (e.g. methyl, ethyl or tert-butyl).

According to another embodiment, (III) provides a compound of a specific formula, wherein R ³ are at each occurrence is independently hydrogen or methyl.

According to another embodiment, there is provided specifically a compound of formula (III), wherein R ¹ is substituted or unsubstituted C _1-8 alkyl, preferably substituted or unsubstituted C _1-4 alkyl, more Preferably, it is an unsubstituted C _1-4 alkyl group (e.g., methyl, ethyl, isopropyl or t-butyl).

According to another embodiment, the compound of formula to provide a particular (III), wherein R ¹ is methyl, ethyl, isopropyl or tert-butyl.

According to another embodiment, there is provided specifically a compound of formula (III), wherein R ¹ is substituted or unsubstituted halo C _1-8 alkyl, preferably unsubstituted halo C _1-8 alkyl (eg 2 , 2,2-trifluoroethyl).

According to another embodiment, (III) provides a compound of a specific formula, wherein R ¹ is 2,2,2-trifluoroethyl.

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein R ¹ is substituted or unsubstituted C _6-14 aryl, preferably substituted or unsubstituted phenyl, and more preferably Substituted phenyl. In this embodiment, the C _6-14 aryl group or the substituent on the phenyl group may be one or more and independently selected from halogen (for example, F, Cl or Br), C _1-4 alkyl (for example, methyl group). Or ethyl) and a halogen C _1-8 alkyl group (e.g., trifluoromethyl).

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein R ¹ is optionally selected from halo (eg F, Cl or Br), C _1-4 alkyl (eg methyl or A phenyl group substituted with a substituent of an ethyl group and a halogen C _1-8 alkyl group (for example, a trifluoromethyl group).

According to another embodiment, the compound of formula to provide a particular (III), wherein R ¹ is the phenyl group and a substituted or more substituents independently selected from fluoro, methyl and trifluoromethyl.

According to another embodiment, there is provided specifically a compound of formula (III), wherein R ¹ is substituted or unsubstituted C _3-12 cycloalkyl, preferably substituted or unsubstituted C _3-6 cycloalkyl More preferably, it is a substituted or unsubstituted cyclohexyl group. In this embodiment, the substituent on the C _3-12 cycloalkyl group, the C _3-6 cycloalkyl group or the cyclohexyl group may be one or more and independently selected from halogen (for example, F, Cl or Br), C. _1-4 alkyl (e.g., methyl) and halogen _C1-8 alkyl (e.g., trifluoromethyl).

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein R ¹ is optionally selected from halogen (eg, F, Cl or Br), C _1-4 alkyl (eg methyl), by one or more And a cyclohexyl group substituted with a substituent of a halogen C _1-8 alkyl group (for example, a trifluoromethyl group).

According to another embodiment, (III) provides a compound of a specific formula, wherein R ¹ is the substituted cyclohexyl group and one or more substituents are independently selected fluoro, methyl and trifluoromethyl.

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein R ¹ is substituted or unsubstituted 5-14 membered heteroaryl, preferably substituted or unsubstituted pyridine, more preferably substituted Pyridine. In this embodiment, the substituent on the pyridine may be one or more and independently selected from halogen (for example, F, Cl or Br), C _1-4 alkyl (for example, methyl, ethyl) and halogen C _{1 . -8} alkyl (e.g., trifluoromethyl).

According to a further embodiment, there is provided in particular a compound of formula (III), wherein R ¹ is optionally selected from one or more selected from the group consisting of halogen (F, Cl or Br), C _1-4 alkyl (eg methyl) and halogen C A pyridine substituted with a substituent of _1-8 alkyl (e.g., trifluoromethyl).

According to another embodiment, (III) provides a compound of a specific formula, wherein R ¹ is substituted pyridyl and substituted with one or more of the group is trifluoromethyl.

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein R ¹ is methyl, ethyl, isopropyl, tert-butyl, 2,2,2-trifluoroethyl, 3-(trifluoromethyl) Phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro- 4-(Trifluoromethyl)phenyl, 6-(trifluoromethyl)pyridin-3-yl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl) Base) cyclohexyl, (1 s , 4 s ) -4-(trifluoromethyl)cyclohexyl or (1 r , 4 r )-4-(trifluoromethyl)cyclohexyl.

According to another embodiment, the compound of formula to provide a particular (III), wherein Q ¹ is N.

According to another embodiment, (III) provides a compound of a specific formula, wherein Q ¹ is CH or CR ^4.

According to another embodiment, a compound of formula (III) is specified, wherein Q ² is CH or CR ⁴ .

According to another embodiment, the compound of formula to provide a particular (III), wherein Q ³ is N or CH.

According to another embodiment, (III) provides a compound of a specific formula, wherein Q ⁴ is CH or CR ^4.

According to another embodiment, the compound of formula to provide a particular (III), wherein Q ¹ is N, CH or CR ^4, Q ² is CH or CR ^4, Q ³ is N or CH, and Q ⁴ is CR ^4.

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein each occurrence of R ⁴ is independently halogen (eg, F, Cl or Br), C _1-4 alkyl (eg methyl or ethyl) Halogen C _1-8 alkyl (eg difluoromethyl) or C _1-8 alkoxy (eg methoxy).

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein each occurrence of R ⁴ is independently OCH ₃ , CH ₃ , CHF ₂ , Cl or F.

According to another embodiment, the compound of formula to provide a particular (III), wherein Q ¹ is N, CH or CR ^4, Q ² is CH or CR ^4, Q ³ is N or CH, and Q ⁴ is CR ^4. In this embodiment, R ⁴ is OCH ₃ , CH ₃ , CHF ₂ , Cl or F.

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein W is substituted or unsubstituted C _1-8 alkyl (eg methyl, ethyl, isopropyl or tert-butyl), halogen C _1-8 alkyl (eg 1-fluoro-2-methylpropan-2-yl), hydroxy C _1-8 alkyl (eg 1-hydroxy-2-methylpropan-2-yl), tetrahydrofuranyl or S )-tetrahydrofuran-2-yl.

According to another embodiment, there is provided specifically provided a compound of formula (III), wherein W is isopropyl, tert-butyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan- 2-Based, tetrahydrofuranyl or ( S )-tetrahydrofuran-2-yl.

According to another embodiment, a compound of formula (III) is specifically provided wherein: Z ¹ is N; Z ³ is CR ² (eg CH) or N; R ¹ is substituted or unsubstituted phenyl, preferably 3 The bit has at least one substitution (eg, -CF ₃ or halogen substitution); R ² and R ³ are as defined above for formula (III), and are preferably hydrogen; Q ¹ , Q ² , Q ³ and Q ⁴ are N, CH or CR ⁴ , wherein at most one of Q ¹ , Q ² , Q ³ and Q ⁴ is N, and Q ¹ , Q ² , Q ³ and Q ^{4 are} preferably independently CH or CR ⁴ , wherein each R ⁴ Is halogen or methyl; and W is as defined above for formula (III) and is preferably a branched alkyl group (e.g., tert-butyl or isopropyl).

According to another embodiment, there is provided a compound of formula (III), wherein: Z ¹ is CR ² (eg CH); Z ³ is N; R ¹ is substituted or unsubstituted phenyl, preferably having 3 positions At least one substitution (eg, -CF ₃ or halogen substitution); R ² and R ³ are as defined above for formula (III), and are preferably hydrogen; Q ¹ , Q ² , Q ³ and Q ⁴ are N, CH or CR ⁴ , wherein at most one of Q ¹ , Q ² , Q ³ and Q ⁴ is N, and Q ¹ , Q ² , Q ³ and Q ^{4 are} preferably independently CH or CR ⁴ , wherein each R ⁴ is halogen Or methyl; and W is as defined above for formula (III) and is preferably a branched alkyl group (e.g., tert-butyl or isopropyl).

The compounds of the invention include the compounds of Examples 1-80.

According to one embodiment, a specific compound of formula to provide (III) embodiment, ₅₀ on which IC mPGES 1-activity value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM.

It is understood that formulas (I), (II), and (III) structurally encompass all geometric isomers, stereoisomers, enantiomers, and diastereoisomers that may be encompassed by chemical structures of the species described herein. Isomers, N -oxides, and pharmaceutically acceptable salts.

The application also provides a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one of the compounds described herein. The compounds described herein can be combined with pharmaceutically acceptable excipients (such as The agent or diluent) is associated or diluted by the carrier or enclosed in a carrier which can be in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions of the invention are useful for inhibiting the activity of mPGES-1 associated with a variety of disease conditions.

The invention further provides a method of inhibiting mPGES-1 in an individual in need thereof by administering to the individual one or more compounds described herein in an amount effective to inhibit the receptor.

definition

The term "halogen" or "halo" means fluoro (fluoro), chloro (chloro), bromo (bromo) or iodine (iodo).

The term "alkyl" means that only carbon and hydrogen atoms are included in the skeleton, contain no unsaturation, have one to eight carbon atoms (ie, C _1-8 alkyl), and are attached to the rest of the molecule by a single bond. Part of a hydrocarbon chain group such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (third Butyl). The term "C _1-6 alkyl" refers to an alkyl chain having from 1 to 6 carbon atoms. The term "C _1-4 alkyl" refers to an alkyl chain having from 1 to 4 carbon atoms. Unless stated or stated to the contrary, all alkyl groups described or claimed herein may be straight or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e., C _2-10 alkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butene base. Unless stated to the contrary or to the contrary, all alkenyl groups described or claimed herein may be straight or branched, substituted or unsubstituted.

The term "alkynyl" refers to a hydrocarbon group having at least one carbon-carbon reference and having from 2 to about 12 carbon atoms (wherein a group having from 2 to about 10 carbon atoms is preferred, i.e., C _2-10 alkyne) base). Non-limiting examples of alkynyl groups include ethynyl, propynyl and butynyl. Unless stated or stated to the contrary, all alkynyl groups described or claimed herein may be straight or branched, substituted or unsubstituted.

The term "alkoxy" denotes an alkyl group (i.e., a C _1-8 alkoxy group) attached to the remainder of the molecule via an oxygen linkage. Representative examples of such groups are -OCH ₃ and -OC ₂ H ₅ . Unless stated or stated to the contrary, all alkoxy groups described or claimed herein may be straight or branched, substituted or unsubstituted.

The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above which is bonded directly to an alkyl group as defined above (ie, _C1-8 alkoxy). C _1-8 alkyl or C _1-8 alkyloxy C _1-8 alkyl). Examples of such alkoxyalkyl moieties include, but are not limited to, -CH ₂ OCH ₃ and -CH ₂ OC ₂ H ₅ . Unless stated or stated to the contrary, all alkoxyalkyl groups described herein may be straight or branched, substituted or unsubstituted.

The term "haloalkyl" refers to at least one halo group (selected from F, Cl, Br or I) attached to an alkyl group as defined above (ie, halo C _1-8 alkyl). Examples of such haloalkyl moieties include, but are not limited to, trifluoromethyl, difluoromethyl, and fluoromethyl. Unless stated or stated to the contrary, all haloalkyl groups described herein may be straight or branched, substituted or unsubstituted.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e., a halogen C _1-8 alkoxy group). Examples of "haloalkoxy" include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, five Chloroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy and 1-bromoethoxy. Unless otherwise stated or recited, all haloalkoxy groups described herein may be straight or branched, substituted or unsubstituted.

The term "hydroxyalkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms are replaced by a hydroxy group (ie, a hydroxy _C1-8 alkyl group). Examples of hydroxy alkyl moieties include (but are not limited _{to) -CH 2 OH, -C 2 H} 4 OH and _{-CH (OH) C 2 H 4} OH.

The term "cycloalkyl" denotes a non-aromatic monocyclic or polycyclic ring system having from 3 to about 12 carbon atoms (i.e., C _3-12 cycloalkyl). Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl, bridged cyclic groups or spirobicyclic groups such as spiro(4,4)indol-2-yl. The term "C _3-6 cycloalkyl" means a ring having 3 to 6 carbon atoms. Unless stated or stated to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkylalkyl" refers to a ring-containing group having 3 to about 8 carbon atoms directly attached to the alkyl group (i.e., C _3-8 cycloalkyl C _1-8 alkyl). A cycloalkylalkyl group can be attached to the main structure at any carbon atom in the alkyl group that results in a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless stated or stated to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to a cyclic group having from 3 to about 8 carbon atoms having at least one carbon-carbon double bond (ie, a C _3-8 cycloalkenyl group). Examples of "cycloalkenyl" include, but are not limited to, cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless stated or stated to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenylalkyl" refers to a cyclic group having from 3 to about 8 carbon atoms (ie, C _3-8 cycloalkenyl C _{1 )} having at least one carbon-carbon double bond bonded directly to the alkyl group. _-8 alkyl). The cycloalkenylalkyl group can be attached to the main structure at any carbon atom in the alkyl group that results in a stable structure. Unless stated or stated to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "aryl" refers to an aromatic group having 6 to 14 carbon atoms (ie, a C _6-14 aryl group), including monocyclic, bicyclic, and tricyclic aromatic systems such as phenyl, naphthyl, and tetra. Hydronaphthyl, indanyl and biphenyl. Unless stated or stated to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.

The term "aryloxy" refers to an aryl group (i.e., C _6-14 aryloxy) as defined above attached to the remainder of the molecule via an oxygen linkage. Examples of aryloxy moieties include, but are not limited to, phenoxy and naphthyloxy. Unless stated or stated to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.

The term "arylalkyl" refers to an aryl group as defined above which is bonded directly to an alkyl group as defined above, that is, a C _6-14 aryl C _1-8 alkyl group, such as -CH ₂ C ₆ H ₅ and- C ₂ H ₄ C ₆ H ₅ . Unless stated or described to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted non-aromatic 3 consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. Up to 15 membered ring groups (ie, 3 to 15 membered heterocyclic groups). The heterocyclic group may be a monocyclic, bicyclic or tricyclic ring system which may include a fused ring, a bridged ring or a spiro ring system, and the nitrogen, phosphorus, carbon, oxygen or sulfur atom in the heterocyclic group may be oxidized as appropriate. Various oxidation states. Furthermore, the nitrogen atom may optionally be quaternized by quaternary; in addition, the heterocyclic or heterocyclic group may optionally contain one or more olefinic bonds, unless otherwise limited by definition. Examples of such heterocyclic groups include, but are not limited to, aziridine, azetidinyl, benzobisoxazolyl, benzodioxanyl, benzohydropyranyl, Dioxapentanyl, dioxaphospholyl, decahydroisoquinolinyl, indanyl, porphyrin, isoindolyl, isobenzohydropyranyl, iso Thiazolidine, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-sided oxypiperazinyl, 2-oxopiperidinyl, 2-sided Oxypyrrolidinyl, 2-oxooxyindolyl, octahydroindenyl, octahydroisodecyl, perhydroazinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, piperidine Pyridyl, phenothiazine, phenoxazinyl, Pyridyl, tetrahydroisoquinolyl, tetrahydrofuranyl, tetrahydropentanyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinium hydrazide and thiamorpholinyl hydrazine. The heterocyclic group can be attached to the main structure at any heteroatom or carbon atom that results in a stable structure. Unless stated or stated to the contrary, all heterocyclic groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic group bonded directly to an alkyl group (i.e., a 3 to 15 membered heterocyclic C _1-8 alkyl group). The heterocyclylalkyl group can be attached to the main structure at any carbon atom in the alkyl group that results in a stable structure. Unless stated or stated to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term "heteroaryl" refers to a substituted or unsubstituted 5 to 14 membered aromatic heterocyclic group having one or more heteroatoms independently selected from N, O or S (also That is 5 to 14 members of heteroaryl). Heteroaryl groups can be monocyclic, bicyclic or tricyclic systems. A heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom that results in a stable structure. Examples of such heteroaryl ring groups include, but are not limited to, oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isodecyl, pyrrolyl, triazolyl, triazinyl , tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzene Imidazolyl, benzothienyl, benzopiperidyl, oxazolyl, quinolyl, isoquinolinyl, quinazolinyl, Alkyl, naphthyridinyl, acridinyl, fluorenyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, pyridazinyl, acridinyl, phenazinyl and pyridazinyl. Unless stated or stated to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring group bonded directly to an alkyl group (i.e., a 5 to 14 membered heteroaryl C _1-8 alkyl group). The heteroarylalkyl group can be attached to the main structure at any carbon atom in the alkyl group that results in a stable structure. Unless stated or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "substituted" as used herein, unless otherwise specified, is substituted by any one or combination of the following substituents: hydroxy, halo, carboxy, cyano, nitro, pendant oxy (=O), sulphur (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, Substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted ring Alkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted Or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, Substituted or unsubstituted heterocyclic ring, substituted or unsubstituted vein, -COOR ^x' , -C(O)R ^x' , -C(S)R ^x' , -C(O)NR ^{x '} R ^{y '} , -C(O)ONR ^x' R ^y' , -NR ^x' CONR ^y' R ^z' , -N(R ^x' )SOR ^y' , -N(R ^x' )SO ₂ R ^{y '} , -(=NN(R ^x' )R ^y' ), -NR ^x' C(O)OR ^y' , -NR ^x' R ^y' , -NR ^x' C(O)R ^y' , -NR ^x' C(S)R ^y' , -NR ^x' C(S)NR ^y' R ^z' , -SONR ^x' R ^y' , -SO ₂ NR ^x' R ^y' , -OR ^x' , -OC (O)NR ^y' R ^z' , -OC(O)OR ^y' , -OC(O)R ^x' , -OC(O)NR ^x' R ^y' , -SR ^x' , -SOR ^x' , -SO ₂ R ^x' and -ONO ₂ , wherein R ^{x '} , R ^{y '} and R ^{z '} are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl a substituted heterocyclylalkyl ring, a substituted or unsubstituted heteroarylalkyl group, and a substituted or unsubstituted heterocyclic ring. Substituents in the "substituted" group mentioned above may not be further substituted. For example, when the substituent on the substituted alkyl group is a substituted aryl group, the substituent on the substituted aryl group may be an unsubstituted alkenyl group but may not be Substituted alkenyl."

The term "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, dextrocamphor, carbonic acid Salt, chloride, clavulanate, citrate, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, propionate lacosyl sulfate (estolate), ethanesulfonate Acid salt, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, Hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isosulfonate, lactate, lactobionate, laurate, malate, maleic acid Salt, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, N -methylglucamine ammonium salt , oleate, oxalate, pamoate/embonate, palmitate, pantothenate, phosphate, diphosphate, polyhalf Lacturonate, salicylate, stearate, sulfate, hypoacetate, succinate, tannate, tartrate, teaclate, tosylate , triethyl iodide and valerate. Examples of salts obtained from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, and zinc.

The term "treating" a condition, disorder or condition includes: (a) preventing or delaying the affliction or predisposition to the condition, disorder or condition but having not experienced or manifested the condition, disorder or condition (a) inhibiting the condition, disorder or condition, ie, arresting or ameliorating the disease or at least one clinical or subclinical thereof, in the clinical or subclinical condition of the individual; Development of the symptoms; or (c) mitigating the disease, that is, causing the condition, condition or condition or at least one of its clinical or subclinical symptoms to subside.

The term "individual" includes mammals (especially humans) and other animals, such as livestock (eg, domestic pets, including cats and dogs) and non-livestock (such as wildlife).

By "therapeutically effective amount" is meant an amount of a compound that is sufficient to effect such treatment when administered to an individual to treat a condition, disorder or condition. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, physical condition, and responsiveness of the individual to be treated.

Pain can be triggered by many physical or chemical stimuli and mediates Sensory neurons that respond to stimuli are called "nociceptors." The pain receptor is a primary sensory afferent (C and Aδ fiber) neuron activated by a wide variety of noxious stimuli including chemical, mechanical, thermal and proton (pH < 6) modalities. The pain receptor is the nerve that senses and reacts to the damaged part of the body. It signals tissue stimuli, impending damage or actual damage. When activated, it transmits a pain signal (via peripheral nerves and spinal cord) to the brain.

The term "chronic pain" generally refers to pain that lasts for 3 months or more and can cause significant changes in the patient's personality, lifestyle, functional ability, and overall quality of life. Chronic pain can be classified as painful or painful pain. Pain-sensitive pain includes tissue-induced pain and inflammatory pain, such as inflammatory pain associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by an abnormal somatosensory conduction process. Pain is usually well defined, persistent, and often has pain or pulsation characteristics. Visceral pain is a subtype of internal organs involved in painful sensation pain. It tends to be paroxysmal and undefined. Pain-sensitive pain is usually limited in time, meaning that when tissue damage is cured, pain is usually eliminated (arthritis is a significant exception because it is not time-limited).

Certain compounds of the present patent application can exist in stereoisomeric forms such as diastereomers and enantiomers. With regard to the overall compounds described by the general formula (I), the invention extends to all such stereoisomeric forms and mixtures thereof. The different stereoisomeric forms of the compounds described herein can be separated from each other by methods known in the art, or the given isomers can be borrowed Obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of the compounds described herein are also contemplated. It will also be appreciated that the compounds described herein may exist in a fused form, such as a hydrate, as well as in an unfused form, and that the invention encompasses all such forms.

Pharmaceutical composition

The compounds of the invention are usually administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures known in the art of pharmacy and comprise at least one compound of the invention. The pharmaceutical compositions of this patent application comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients. Generally, pharmaceutically acceptable excipients are approved by regulatory agencies or are generally considered safe for human or animal use. Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, tackifiers, and solvents.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, white earth, sucrose, dextrin, magnesium carbonate, sugar, amylose, stearin Magnesium silicate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ether of cellulose, citric acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride, fatty acid ester And polyethylene oxide.

The pharmaceutical compositions may also include one or more pharmaceutically acceptable adjuvants, wetting agents, suspending agents, preservatives, buffering agents, sweetening agents, flavoring agents, coloring agents or any combination of the foregoing.

The pharmaceutical composition may be in a conventional form, such as a capsule, a lozenge, a solution, Suspensions, injectables or products for topical application. Additionally, the pharmaceutical compositions of the present invention can be formulated to provide a desired release profile.

Administration of a compound of the invention in neat form or in the form of a suitable pharmaceutical composition can be carried out using any of the routes of administration of the pharmaceutical compositions. The route of administration can be any route for the effective delivery of the active compound of the present application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, transdermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or transsurface.

Solid oral formulations include, but are not limited to, lozenges, capsules (soft or hard gelatin), dragees (containing active ingredients in powder or pellet form), tablets and buccal tablets.

Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids such as suspensions or solutions.

The surface preparations of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, impregnated dressings, and may contain suitable conventional additives, such as preservatives, to aid in the administration of the drug. Penetrating solvent.

Pharmaceutical compositions of the present patent application can be prepared, for example, by conventional techniques as described in Remington: The Science and Practice of Pharmacy , 20th Edition, 2003 (Lippincott Williams & Wilkins).

Dosages of the compounds suitable for the treatment of the diseases and conditions described herein can be determined by those skilled in the art. The therapeutic dose is typically identified by performing a dose range study in humans based on prima facie evidence obtained from animal studies. The dosage must be sufficient to produce the desired therapeutic benefit without causing undesirable side effects. The mode of administration, dosage form and suitable pharmaceutical excipients can also be suitably used and adjusted by those skilled in the art. All changes and modifications are contemplated as being within the scope of this patent application.

In another embodiment, the invention is directed to a pharmaceutical composition comprising a compound as described herein, a second therapeutic agent, and optionally a pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition comprises a compound as described herein and a second therapeutic agent, wherein each of the compound described herein and the second therapeutic agent is mixed with a pharmaceutically acceptable excipient. Provisioning.

treatment method

The compounds of the invention are particularly useful because they inhibit the activity of prostaglandin E synthetase {and, in particular, microsomal prostaglandin E synthetase-1 (mPGES-1)}, ie, prevent, inhibit or inhibit mPGES-1 or The mPGES-1 enzyme forms a complex as part of it and/or can initiate mPGES-1 modulating effects. Thus, the compounds of the invention are useful in the treatment of such conditions in which it is desired to inhibit PGES, and in particular mPGES-1.

Accordingly, the compounds of the invention are expected to be useful in the treatment of inflammation. The term "inflammation" will be understood by those skilled in the art to include any condition characterized by a local or systemic protective response which may be caused by physical trauma, infection, chronic disease (such as those mentioned above), and/or The chemical and/or physiological response of an external stimulator (eg, as part of an allergic reaction) is initiated. Any such reaction that can be used to destroy, dilute or sequester both the damaging agent and the damaged tissue can manifest itself as, for example, fever, swelling, pain, redness, Vasodilation and/or increased blood flow.

The term "inflammation" is also understood to include any inflammatory disease, disorder or condition itself, any condition having an inflammatory component associated therewith, and/or any condition characterized by inflammation as a symptom, including, inter alia, Acute, chronic, ulcerative, specific, allergic infections caused by pathogens; immune responses due to allergies, foreign body entry, body damage and necrotizing inflammation; and other inflammatory forms known to those skilled in the art. Thus, for the purposes of the present invention, the term also includes inflammatory pain, general pain and/or fever.

The compounds of the invention may also be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, lower back pain , fibromyalgia, myofascial disorders, viral infections (eg influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgery or dental procedures, malignant tumors (eg breast, colon and prostate cancer), high prostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, rheumatic fever, joint adhesion spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, Scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes, neurodegenerative disorders (such as Alzheimer's disease (A Lzheimer's disease) and multiple sclerosis), autoimmune Diseases, allergic conditions, rhinitis, ulcers, mild to moderate active ulcerative colitis, familial adenoma multiple polyps, coronary heart disease, sarcoma-like disease, and any other disease with inflammatory components.

The compounds of the invention may also have effects that are not associated with inflammatory mechanisms, such as reducing bone loss in an individual. Conditions which may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal disease.

Since the compounds of the present invention have mPGES-1 inhibitory activity, the compounds are useful for alleviating pain, fever and inflammation in a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, the common cold, Lower back and neck pain, dysmenorrhea, headache, migraine (acute and preventive treatment), toothache, sprain and strain, myositis, neuralgia, synovitis, arthritis (including rheumatoid arthritis, youth rheumatoid Arthritis, degenerative joint disease (osteoarthritis), acute gout and joint adhesion spondylitis), acute, subacute and chronic musculoskeletal pain syndrome (such as bursitis, burns, injuries and surgery (postoperative pain) ) and pain after the dental procedure) as well as the pain of the first treatment. Pain can be mild pain, moderate pain, severe pain, musculoskeletal pain, complex area pain syndrome, neuropathic pain, back pain (such as acute visceral pain), neuropathy, acute trauma, chemotherapy-induced mononephropathy, Polyneuropathy pain conditions (such as diabetic peripheral neuropathy and chemotherapy-induced neuropathy), autonomic neuropathic pain conditions, peripheral nervous system (PNS) lesions or central nervous system (CNS) lesions or disease-related pain conditions, cervical, lumbar or sciatic nerves Painful multiple radiculopathy, horsetail Cauda equina syndrome, piriformis syndrome, paraplegia, limb paralysis, pain conditions associated with various polyneuritis conditions lurking under various infections, chemical damage, radiation exposure, latent disease or lack of condition ( Such as beriberi, vitamin deficiency, hypothyroidism, porphyria, cancer, HIV, autoimmune diseases (such as multiple sclerosis and spinal cord injury), fibromyalgia, nerve damage, ischemia , neurodegeneration, stroke, post-stroke pain, inflammatory disease, esophagitis, gastroesophageal reflux disease (GERD), septic bowel syndrome, inflammatory bowel disease, pelvic allergy, urinary incontinence, cystitis, gastroduodenal ulcer, muscle Pain, pain due to colic and involvement in pain. The compounds of the invention may also be useful in the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.

The compounds of the present invention will also inhibit prostaglandin-induced smooth muscle contraction by preventing the synthesis of contractile prostaglandins and are therefore useful for the treatment of dysmenorrhea, premature labor and asthma.

Furthermore, the compounds of the invention inhibit cell xenogenic transformation and metastatic tumor growth and are therefore useful in the treatment of cancer and cancer associated pain. Furthermore, the invention provides a preferred embodiment of the methods and uses as described herein, wherein the cancer comprises acute lymphoblastic leukemia, acute myeloid leukemia, juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytes Tumor, atypical teratoma, basal cell carcinoma, cholangiocarcinoma, extrahepatic cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt Lymphoma, class Carcinoma tumor, unknown primary cancer, cardiac (Cardiac/Heart) tumor, medium Central nervous system tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma , bile duct extrahepatic cancer, ductal carcinoma in situ, embryonic tumor, central nervous system cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing Sarcoma, Extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, bone fibrous histiocytoma, malignant tumor and osteosarcoma, gallbladder cancer, stomach (Gastric/Stomach) cancer, gastrointestinal carcinoma, gastrointestinal Matrix tumors, germ cell tumors, Gestational Trophoblastic Tumor, glioma, hairy cell leukemia, head and neck cancer, heart cancer, hepatocyte (hepatic) cancer, histiocytosis, Langerhans Cell (Langerhans Cell) disease, Hodgkin's lymphoma, hypopharyngeal carcinoma, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma (Ka Posi Sarcoma), kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and mouth Cancer, liver cancer, lobular carcinoma in situ, lung cancer, AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system (CNS) lymphoma, macroglobulin Hyperglobulinemia, Waldenström disease, male breast cancer, malignant fibrous histiocytoma and osteosarcoma, melanoma, Merkel Cell Carcinoma, mesothelioma, malignant tumor, Recessive primary metastatic squamous neck cancer And NUT gene Midline Tract Carcinoma Involving NUT Gene, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma neoplasms, Mlycosis Fungoides, myelodysplastic syndrome , myelodysplasia / myeloproliferative neoplasms, myeloid leukemia, chronic, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasal and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodge Gold lymphoma, non-small cell lung cancer, oral cancer, oral cancer, lip and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cavity Cancer, parathyroid carcinoma, penile cancer, pharyngeal carcinoma, pheochromocytoma, pituitary tumor, plasma cell tumor/multiple myeloma, pleural pulmonary blastoma, pregnancy and breast cancer, primary central nervous system Systemic (CNS) lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, renal pelvis and ureteral cancer, transitional cell carcinoma, retinoblastoma, transverse Sarcoma, salivary gland cancer, Ewing sarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, uterine sarcoma, Sézary Syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, scale Cell carcinoma, recessive primary squamous neck cancer, metastatic gastric cancer, T-cell lymphoma, skin cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis and ureteral transitional cell carcinoma, nourishment Maternal tumor, ureter and renal pelvis, unknown primary cancer, transitional cell carcinoma, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, genital cancer, Waldenstrom disease, macroglobulinemia Wilms Tumor And women's cancer.

The compounds of the invention are indicated for the therapeutic and/or prophylactic treatment of the above mentioned conditions. For the therapeutic use mentioned above, the dosage administered will of course vary with the compound employed, the mode of administration, the condition to be treated, and the condition indicated. The daily dose of the compound of the invention may range from 0.05 mg/kg to 100 mg/kg.

General preparation method

The compounds described herein, including the compounds of formula (I), (II) and (III), can be prepared by techniques known to those skilled in the art via the reaction sequences described in the schemes provided below, as well as by other methods. Further, in the following schemes referring to specific acids, bases, reagents, coupling agents, solvents, etc., it is understood that other suitable acids, bases, reagents, coupling agents and the like can be used and are included in the scope of the present invention. Modifications to reaction conditions such as temperature, reaction duration or combinations thereof are contemplated as part of the invention. The purity of the compound obtained by using the general reaction sequence may not be sufficient. Such compounds can be purified by any method known in the art for purifying organic compounds, such as crystallization or tantalum or alumina column chromatography using different solvents in suitable ratios. All possible geometric isomers and stereoisomers are contemplated within the scope of the invention.

Starting materials for the following reaction schemes are commercially available or can be prepared according to methods known to those skilled in the art or by the methods disclosed herein. In general, the intermediates and compounds of the present application can be prepared using the following reaction schemes, wherein all symbols are as defined above.

a compound of formula (I) wherein Z ¹ , Z ² , Z ³ , G ¹ , G ² , G ³ , R ¹ , R ⁴ , m, A, L, W are as defined for the compound of formula (I) and Y The synthesis of NR ^c or O) can be carried out as described in Synthetic Scheme 1. a compound of formula (1) (wherein X represents a suitable leaving group such as Br, Cl, I, OLG, SR ' , S(O)R ' or S(O) ₂ R ' ; wherein LG or R ' is an alkyl group For example, CH ₃ ) and a compound of formula (2) are suitable under conditions known in the art, such as, for example, in acetonitrile (CH ₃ CN), N,N -dimethylformamide (DMF), isopropanol ( Suitable solvents for ⁱ PrOH), tetrahydrofuran (THF) or N -methylpyrrolidone (NMP), in the temperature range of 0-250 ° C or at reflux temperature, as appropriate in a suitable base such as NaH or potassium carbonate The reaction in the presence provides a compound of formula (3). Alternatively, when X represents OH, the conversion of the compound of formula (1) to the compound of formula (3) can be used, for example, benzotriazol-1-yl-oxy-para-(dimethylamino)-indole (BOP). Or a suitable coupling reagent for hexafluorophosphate (benzotriazol-1-yloxy)tris(N-pyrrolidinyl)fluorene (PyBOP) in such as 1,8-diazabicyclo[5.4.0] eleven 7-ene (DBU) or N, N - diisopropylethylamine (DIPEA) for the presence of a base, such as DMF or CH ₃ CN of a suitable solvent, carried out in the temperature range 0-150 ℃.

The nitro group of the compound of the formula (3) may be a suitable reducing agent such as iron and ammonium chloride or Pd/carbon, under H ₂ gas, in a suitable solvent such as ethanol and/or water or ethyl acetate, in a temperature range of 0. Reduction at -150 ° C to provide the amine of formula (4).

Under suitable reaction conditions, a suitable compound of the formula (5) is used (wherein LG represents a suitable leaving group (for example OH or Cl or Br or O-alkyl or O-aryl or O(C=O)-alkane) Treatment of the amine (4) can provide a compound of formula (I). When LG represents OH, the reaction can be carried out using suitable coupling reagents known in the art, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), such as DMF or tetrahydrofuran ( Suitable solvents for THF) are carried out in the temperature range of 0-120 ° C, optionally in the presence of a suitable base such as DIPEA (diisopropylethylamine) or Et ₃ N. Alternatively, the reaction can be carried out in a suitable solvent such as DIPEA or Et ₃ N using a suitable reagent such as isobutyl chloroformate, ethylene dichloride or sulfinium chloride in a suitable solvent such as DMF, DCM or THF. When LG represents Cl, the reaction can be carried out in a suitable solvent such as DMF, DCM or THF at a temperature ranging from 0 to 120 ° C, optionally in the presence of a suitable base such as DIPEA. Further, when LG represents an O-alkyl or O-aryl group or an O(C=O)-alkyl group, the reaction may be carried out using a suitable reagent such as trimethylaluminum or a strong base such as sodium hydride (NaH) such as toluene or DMF is carried out in a suitable solvent.

a compound of the formula (II) wherein Z ¹ , Z ³ , G ¹ , R ¹ , R ² , R ³ , Q ¹ , Q ² , Q ³ , Q ⁴ , R ^x , R ^y , n and W are as defined above The synthesis of (II) a compound and wherein Y is O, NH or NR ^c ) can be carried out as described in Synthetic Scheme 2.

a compound of formula (6) wherein X represents a suitable leaving group such as Br, Cl, I, OLG, SR ' , S(O)R ' or S(O) ₂ R ' ; wherein LG or R ' is alkyl For example, CH ₃ ) and a compound of formula (2) are suitable under the conditions of the art, such as, for example, in acetonitrile (CH ₃ CN), N,N -dimethylformamide (DMF), isopropanol ( ⁱ⁾ Suitable solvents for PrOH), tetrahydrofuran (THF) or N -methylpyrrolidone (NMP), in the temperature range of 0-250 ° C or at reflux temperature, optionally in the presence of a suitable base such as NaH or potassium carbonate The lower reaction provides a compound of formula (7). Alternatively, when X represents OH, the conversion of the compound of formula (6) to the compound of formula (7) can be used, for example, benzotriazol-1-yl-oxy-para-(dimethylamino)-hydrazine hexafluorophosphate (BOP). Or a suitable coupling reagent for hexafluorophosphate (benzotriazol-1-yloxy)tris(N-pyrrolidinyl)fluorene (PyBOP) in such as 1,8-diazabicyclo[5.4.0] eleven 7-ene (DBU) or N, N - diisopropylethylamine (DIPEA) for the presence of a base, such as DMF or CH ₃ CN of a suitable solvent, carried out in the temperature range 0-150 ℃.

The nitro group of the compound of the formula (7) may be a suitable reducing agent such as iron and ammonium chloride or Pd/carbon, under H ₂ gas, in a suitable solvent such as ethanol and/or water or ethyl acetate, in a temperature range of 0. Reduction at -150 ° C to provide the amine of formula (8). Treatment of the amine (8) with a suitable hydrazino compound of the formula (9) wherein LG represents OH or Cl or Br or O-alkyl or O-aryl or O(C=O)-alkyl, under suitable reaction conditions. Compounds of formula (II) can be provided. When LG represents OH, the reaction can be carried out using suitable coupling reagents known in the art, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), such as DMF or tetrahydrofuran ( Suitable solvents for THF) are carried out in the temperature range of 0-120 ° C, optionally in the presence of a suitable base such as DIPEA or Et ₃ N. Alternatively, the reaction can be carried out in a suitable solvent such as DIPEA or Et ₃ N using a suitable reagent such as isobutyl chloroformate, ethylene dichloride or sulfinium chloride in a suitable solvent such as DMF, DCM or THF. When LG represents Cl, the reaction can be carried out in a suitable solvent such as DMF, DCM or THF at a temperature ranging from 0 to 120 ° C, optionally in the presence of a suitable base such as DIPEA. Further, when LG represents an O-alkyl or O-aryl group or an O(C=O)-alkyl group, the reaction may be carried out using a suitable reagent such as trimethylaluminum or a strong base such as sodium hydride (NaH) such as toluene or DMF is carried out in a suitable solvent.

Synthesis of a compound of formula (III) wherein Y, Z ¹ , Z ³ , R ¹ , R ² , R ³ , Q ¹ , Q ² , Q ³ , Q ⁴ and W are as defined above for the compound of formula (III) This can be carried out as described in the synthesis scheme 3.

Synthesis process 3

a compound of formula (10) wherein X represents a suitable leaving group such as Br, Cl, I, OLG, SR ' , S(O)R ' or S(O) ₂ R ' ; wherein LG or R ' is alkyl For example, CH ₃ ) and a compound of formula (2) are suitable under conditions known in the art, such as, for example, in acetonitrile (CH ₃ CN), N,N -dimethylformamide (DMF), isopropanol ( Suitable solvents for ⁱ PrOH), tetrahydrofuran (THF) or N -methylpyrrolidone (NMP), in the temperature range of 0-250 ° C or at reflux temperature, as appropriate in a suitable base such as NaH or potassium carbonate The reaction in the presence provides a compound of formula (11). Alternatively, when X represents OH, the conversion of the compound of formula (10) to the compound of formula (11) can be used, for example, benzotriazol-1-yl-oxy-para-(dimethylamino)-indole (BOP). Or a suitable coupling reagent for hexafluorophosphate (benzotriazol-1-yloxy)tris(N-pyrrolidinyl)fluorene (PyBOP) in such as 1,8-diazabicyclo[5.4.0] eleven 7-ene (DBU) or N, N - diisopropylethylamine (DIPEA) for the presence of a base, such as DMF or CH ₃ CN of a suitable solvent, carried out in the temperature range 0-150 ℃.

The nitro group of the compound of the formula (11) may be a suitable reducing agent such as iron and ammonium chloride or Pd/carbon, under H ₂ gas, in a suitable solvent such as ethanol and/or water or ethyl acetate, in a temperature range Reduction in the range of 0-150 ° C to provide the amine of formula (12). Treatment of the amine (12) with a suitable hydrazino compound of the formula (13) wherein LG represents OH or Cl or Br or O-alkyl or O-aryl or O(C=O)-alkyl, under suitable reaction conditions. Compounds of formula (III) can be provided. When LG represents OH, the reaction can be carried out using suitable coupling reagents known in the art, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), such as DMF or tetrahydrofuran ( Suitable solvents for THF) are carried out in the temperature range of 0-120 ° C, optionally in the presence of a suitable base such as DIPEA or Et ₃ N. Alternatively, the reaction can be carried out in a suitable solvent such as DIPEA or Et ₃ N using a suitable reagent such as isobutyl chloroformate, ethylene dichloride or sulfinium chloride in a suitable solvent such as DMF, DCM or THF. When LG represents Cl, the reaction can be carried out in a suitable solvent such as DMF, DCM or THF at a temperature ranging from 0 to 120 ° C, optionally in the presence of a suitable base such as DIPEA. Further, when LG represents an O-alkyl or O-aryl group or an O(C=O)-alkyl group, the reaction may be carried out using a suitable reagent such as trimethylaluminum or a strong base such as sodium hydride (NaH) such as toluene or DMF is carried out in a suitable solvent.

Synthesis of a compound of formula (III) wherein Y, Z ¹ , Z ³ , R ¹ , R ² , R ³ , Q ¹ , Q ² , Q ³ , Q ⁴ and W are as defined above for the compound of formula (III) This can be carried out as described in the synthesis scheme 4.

Synthesis process 4

a compound of the formula (12) and a compound of the formula (14) wherein LG represents OH or Cl or O-alkyl or O-aryl or O(C=O)-alkyl are in suitable conditions (eg, step 1 of Synthetic Scheme 3) The coupling under the above) provides a compound of formula (15). Further deprotection of the compound of formula (15) using a suitable deprotecting agent such as HCl will provide a compound of formula (16). Compound (16) and a compound of formula (17) wherein LG represents OH or Cl or O-alkyl or O-aryl or O(C=O)-alkyl are in suitable conditions (eg, step 3 of Synthetic Scheme 3) The coupling of the above can provide a compound of formula (III).

experiment

Unless stated otherwise, the processing comprised between the organic and aqueous phase indicated within parenthesis reaction mixture was partitioned, (Na ₂ SO ₄₎ and the layers separated The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purification, unless otherwise mentioned, includes purification by the use of silica gel chromatography techniques in a suitable solvent having the appropriate polarity as the mobile phase. The chemical description and the abbreviations used in the following examples are: AcOH: acetic acid; DMSO- d ₆ : hexamethylene dimethyl hydrazine; CDCl ₃ : deuterated chloroform; CHCl ₃ : chloroform; EtOAc or EA: ethyl acetate; DCM : dichloromethane; DMSO: dimethyl hydrazine; DMF: N,N -dimethylformamide; DMA: dimethylacetamide; DIPEA: N,N -diisopropylethylamine; EDCl:1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOBt: hydroxybenzotriazole; K ₂ CO ₃ : potassium carbonate; LDA: lithium diisopropylamide; MeOH: methanol EtOH: ethanol; NaHCO ₃ : sodium hydrogencarbonate; Na ₂ CO ₃ : sodium carbonate; NaOtBu: sodium butoxide; NMP: N -methylpyrrolidone; PCl ₅ : phosphorus pentachloride; POCl ₃ : oxygen Phosphorus chloride; THF: tetrahydrofuran; TEA: triethylamine; TBAF: tetra-n-butylammonium fluoride; J : coupling constant in units of Hz; RT or rt: room temperature (22-26 ° C); aq.: Aqueous solution; equiv. or eq.: equivalent; conc.: concentrated; ie: ie; h: hour; J : coupling constant in units of Hz.

Preparation of intermediates Intermediate 1

N ¹ -(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

Step 1: Preparation of 1-chloro-5-nitroisoquinoline

In concentrated H ₂ SO ₄ (24 mL) in a solution of 1-chloro-wise to the isoquinoline (3.6 g, 22.09 mmol) dropwise at 0-5 deg.] C was added concentrated HNO ₃ (8 mL). KNO ₃ (2.90 g, 28.71 mmol) was then added portionwise to the reaction mixture at 0-5 °C. The reaction mass was stirred at room temperature for 2 hours and diluted with water, then the reaction mixture was filtered. The filter cake was dissolved in chloroform containing 5% methanol, and dried in Na ₂ SO _4. The organic layer was filtered and concentrated to give 4.0 g of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.74 (t, J = 6.9 Hz, 2H), 8.55 (d, J = 6.3 Hz, 1H), 8.32 (d, J = 6.0 Hz, 1H), 8.02 (t, J = 8.1 Hz, 1H).

Step 2: Preparation of 5-nitro- N- (3-(trifluoromethyl)phenyl)isoquinolin-1-amine

Add 3-(trifluoromethyl)aniline (917 mg, 5.7) to a solution of 1-chloro-5-nitroisoquinoline (1.0 g, 4.8 mmol) in N -methylpyrrolidone (2 mL) Mm). The reaction mass was heated at 110 ° C for 2 hours. The reaction mass was diluted with water and extracted with chloroform. Dry, filter, concentrate and purify the organic layer by column chromatography to give the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.44 (d, J = 7.8 Hz, 1H), 8.33-8.29 (m, 2H), 7.96-7.89 (m, 3H), 7.68 (t, J = 8.1 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.26 (m, 1H).

Step 3: Preparation of N ¹ -(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

Solution of 5-nitro - N - (3- (trifluoromethyl) phenyl) isoquinolin-1-amine (1.0 g, 3.0 mmol) in FtOH: H ₂ O of the mixture (8: 2,10 mL) Iron powder (1.26 g, 4.8 mmol) and NH ₄ Cl (1.6 g, 30.0 mmol) were added to the solution. The reaction mass was heated under reflux for 2 hours and filtered. The filtrate was concentrated and the residue was purifiedjjjjjjjjjj ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.18 (s, 1H), 8.35 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H) ), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.42 - 7.24 (m, 3H), 6.86 (d, J = 7.5 Hz, 1H), 5.84 (s) , 2H).

Intermediate 2

6-chloro-2-fluoro-3-(pentamylaminomethyl)benzoic acid

Step 1: Preparation of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate

Add ⁿ BuLi (27 mL, 43.0 mmol, 1.6 M in hexanes) to a solution of DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) Warm to 0 °C. The reaction mixture was then cooled to -78 ° C and a solution of ethyl 2-chloro-6-fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL). The resulting mixture was stirred at -78 °C for 2 hr then DMF (14 mL, 186 mmol) The resulting mixture was stirred at -78 °C for 1 hour and then gradually warmed to 0 °C over 1 hour. The reaction was quenched with 10% aq. The organic layer was washed with water and brine, dried, dried, filtered and concentrated to afford ethyl 6-chloro-2-fluoro-3-carbylbenzoate. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.27 (s, 1H), 8.05-8.00 (t, J = 7.8 Hz, 1H), 7.72-7.69 (d, J = 8.4 Hz, 1H), 4.53 -4.46 (q, J = 6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J = 6.6 Hz, 3H). Ethyl 6-chloro-2-fluoro-3-carboxybenzoic acid (4.04 g, 17.52 mmol) and hydroxylamine (50% aq., 4.29 mL, 70 mmol) in MeOH (60 mL) The mixture was 1.5 hours. The mixture was then concentrated and the residue diluted with EtOAc EtOAc. The organic layer was separated, dried, filtered and concentrated to give ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.78-7.83 (t, J = 8.1 Hz, 1H), 7.49-7.46 (d, J = 8.4 Hz, 1H), 4.44-4.37 (q, J = 7.5, 14.1 Hz, 2H), 1.34-1.29 (t, J = 7.2 Hz, 3H). Ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10 N HCl A mixture of EtOH (51.42 mL, 51. Further Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated under reflux for 2 h and then stirred at room temperature for 16 h. The reaction mixture was then concentrated. The residue was diluted with EtOAc and the solution was treated with saturated NaHCO _3. The mixture was filtered and dried, dried, filtered andEtOAc evaporated ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.54 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 4.45 (q, J = 7.5, 14.1 Hz, 2H), 4.11 (d, J = 3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, J = 7.2 Hz, 3H).

Step 2: Preparation of ethyl 6-chloro-2-fluoro-3-(pentamylamino)benzoate

Add Et ₃ N (0.105 mL, 0.76 mmol) and three to a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (70 mg, 0.3 mmol) in THF (3 mL) Methyl acetyl chloride (38 μL, 0.31 mmol). The reaction was stirred at room temperature for 2 hr then diluted with EtOAc EtOAc. The organic layer was separated, dried, filtered and concentrated to give &lt ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.15 (brt, 1H), 7.43-7.35 (m, 2H), 4.38 (q, J = 7.2 Hz, 2H), 4.26 (d, J = 5.7 Hz, 2H), 1.30 (t, J = 6.9 Hz, 3H), 1.11 (s, 9H).

Step 3: Preparation of 6-chloro-2-fluoro-3-(pentamylaminomethyl)benzoic acid

To ethyl 6-chloro-2-fluoro-3-(p-amylaminomethyl)benzoate (100 mg, 0.317 mmol) in THF:MeOH:H ₂ O (3:2:1; 6 mL) NaOH (25 mg, 0.634 mmol) was added to the solution. The reaction mass was stirred at room temperature for 3 hours. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and washed with water and brine. The organic layer was separated, dried, filtered and concentrated to give &lt ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 14.10 (s, 1H), 8.14 (brt, 1H), 7.38-7.26 (m, 2H), 4.25 (d, J = 5.4 Hz, 2H), 1.11 (s, 9H).

Intermediate 3

3-chloro-6-(pentamylaminomethyl)pyridinecarboxylic acid

Step 1: Preparation of ethyl 3-chloro-6-iodopyridinecarboxylate

To 3,6-dichloro-pyridine carboxylic acid ethyl ester (5.0 g, 24 mmol) was added Nal (10 g, 66.7 mmol) and acetyl chloride (2.5 mL) in (45 mL) in a solution of CH ₃ CN in. The reaction mass was heated in a sealed tube at 100 ° C for 48 hours. The reaction material was diluted with EtOAc and washed with Na ₂ S ₂ O ₃ and saturated solution of NaHCO _3. The organic layer was separated, dried, filtered and concentrated to give 2 g of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.04 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 4.38 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 6.9 Hz, 3H).

Step 2: Preparation of ethyl 3-chloro-6-cyanopyridinecarboxylate

To a solution of 3-chloro-6-iodopyridinium methanecarboxylate (1.6 g, 5.38 mmol) in pyridine (40 mL), CuCN (480 mg, 5. The reaction mass was heated at 80 ° C for 6 hours. Water was then added to the reaction mass and it was extracted with EtOAc. The organic layer was separated, dried, filtered and evaporated elut ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.44 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).

Step 3: Preparation of ethyl 6-(((t-butoxycarbonyl)amino)methyl)-3-chloropyridinecarboxylate

To a solution of ethyl 3-chloro-6-cyanopicolinate (1.0 g, 4.76 mmol) in ethanol (25 mL) was added Pt/C (1 g) and dibutyl succinate (1.037 g, 4.76 mmol). The reaction mass was hydrogenated at 60 psi for 18 hours. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.06 (d, J = 8.4 Hz, 1H), 7.56 (brt, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.36 (q, J = 6.9 Hz, 2H), 4.21 (d, J = 6.0 Hz, 2H), 1.39-1.17 (m, 12H).

Step 4: Preparation of ethyl 3-chloro-6-(pentamylaminomethyl)pyridinecarboxylate

Ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-3-chloropicolinate (100 mg, 0.318 mmol) was stirred in EtOAc (1 mL) The solution was 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in CH ₂ Cl _{2 (2} mL) in. The solution was treated with DIPEA (0.5 mL) and trimethylethylphosphonium chloride (38 mg, 0.318 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with H ₂ O and brine. The organic layer was separated, dried, filtered and concentrated to give &lt ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.26 (brt, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 4.40-4.31 ( m, 4H), 1.33-1.10 (m, 12H).

Step 5: Preparation of 3-chloro-6-(pentamylaminomethyl)pyridinecarboxylic acid

Ethyl 3-chloro-6-(p-amylaminomethyl) picolinate (1.00 g, 3.35 mmol) in THF:MeOH:H ₂ O (3:2:1; 6 mL) and EtOAc The title compound was prepared following the procedure described in Step 3 of Intermediate 2 to afford 750 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 13.85 (br s, 1H), 8.25 (brt, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.1 Hz , 1H), 4.32 (d, J = 6.0 Hz, 2H), 1.19 (s, 9H).

Intermediate 4

2,6-Dimethyl-3-(pentamylaminomethyl)benzoic acid

Step 1: Preparation of 2,6-dimethyl-3-((2,2,2-trifluoroethylamino)methyl)benzoic acid

(, 13.33 mmol 2.0 g) in concentrated H ₂ SO ₄ was added 2,2,2-trifluoroethyl (4 mL) in a solution of 2,6-dimethylbenzoic acid - N - (hydroxymethyl) acetyl Amine (2.1 g, 13.33 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water and stirred for 2 hours. The precipitate was collected by filtration and dried to give 3.2 g of title product. ^{1 H NMR (300 MHz, DMSO-} d 6): δ 9.92 (m, 2H), 7.15-7.04 (m, 2H), 4.36 (s, 2H), 2.18 (m, 6H).

Step 2: Preparation of 2,6-dimethyl-3-(pentamylamino)benzoic acid

Add 1 N HCl to a solution of 2,6-dimethyl-3-((2,2,2-trifluoroethylamino)methyl)benzoic acid (3.2 g) in THF (15 mL) 15 mL) and the reaction mass was heated under reflux for 3 hours. The reaction mixture was concentrated and the crude material was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj To a solution of 3-(aminomethyl)-2,6-dimethylbenzoic acid (500 mg, 2.46 mmol) in THF was added N,O -bis(trimethyldecyl)trifluoroacetamide ( 948 mg, 3.69 mmol) and the reaction mass was heated under reflux for 20 min. The reaction mass was cooled to 0 ℃ and sequentially added _{Et 3 N (1.77 mL, 9.85} mmol) and trimethyl acetyl chloride (0.44 mL, 3.69 mmol). The reaction mixture was stirred at room temperature for 18 hr then quenched with water and EtOAc. The organic layer was separated, dried, filtered and concentrated to give &lt ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 13.15 (br s, 1H), 7.93 (br, 1H), 7.08-7.01 (m, 2H), 4.19 (d, J = 5.7 Hz, 2H) , 2.21 (s, 3H), 2.17 (s, 3H), 1.12 (s, 9H).

Intermediate 5

2-chloro-5-(pentamylaminomethyl)benzoic acid

Step 1: Preparation of 2-chloro-5-{[(trifluoroethenyl)amino]methyl}benzoic acid

Was added to 2-chlorobenzoic acid (500 mg, 3.49 mmol) in concentrated H ₂ SO ₄ in the solution of 2,2,2-trifluoro - N - (hydroxymethyl) acetyl amine (547 mg, 3.49 mmol) . The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water and the obtained precipitate was collected by filtration, dried and recrystallized from toluene/butan-2-one (7:1) to give 800 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 13.47 (br s, 1H), 10.06 (br s, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.43 ( d, J = 9.9 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H); MS (m/z): 280.18 (MH) ^- .

Step 2: Preparation of 5-{[(t-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid

2-Chloro-5-{[(trifluoroethenyl)amino]methyl}benzoic acid (800 mg, 2.84 mmol) in EtOAc (5 mL) The solution was 12 hours. The reaction mixture was concentrated and the concentrate was dissolved in THF (10 mL). The solution was treated with NaOH (284 mg, 7.10 mmol) in H2O (1 mL) and _&lt; RTI ID=0.0&gt;&gt _; The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified with 1 N HCl and the pH was adjusted to 2-3. The reaction mixture was washed with 5% MeOH in CHCl ₃ extraction of. The organic layer was separated, dried, filtered and concentrated. The concentrate was recrystallized from toluene/butan-2-one (7:1) to give 800 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 13.1 (br s, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H) ), 4.13 (d, J = 5.7 Hz, 2H), 1.38 (s, 9H); MS (m/z): 283.94 (MH) ^- .

Step 3: Preparation of methyl 5-(((t-butoxycarbonyl)amino)methyl)-2-chlorobenzoate

To a solution of 5-{[(t-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (1.0 g, 3.50 mmol) in DMF (5.0 mL) 3.50 mmol) and K ₂ CO ₃ (966 mg, 7.00 mmol). The reaction mass was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to give 440 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 7.66 (s, 1H), 7.49-7.52 (m, 2H), 7.42 (d, J = 6.3 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 1.38 (s, 9H).

Step 4: Preparation of methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride

Methyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-chlorobenzoate (100 mg, 0.334 mmol) was stirred in EtOAc (1 mL) The solution was 2 hours. The reaction mixture was concentrated and triturated with pentane to give &lt ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.20 (br s, 3H), 7.95 (s, 1H), 7.67 (s, 2H), 4.40 (s, 2H), 3.88 (s, 3H).

Step 5: Preparation of methyl 2-chloro-5-(pentamylaminomethyl)benzoate

Use methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (1.80 g, 6.00 mmol), DIPEA (3.096 g, 2.4 mmol) and trimethylethyl chlorobenzene (1.2 mL, 9.0 mmol) The title compound was prepared in THF (20 mL) elute ¹ H NMR (300 MHz, DMSO d ₆ ): 8.16 (m, 1H), 7.65 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 4.25 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 1.15 (s, 9H).

Step 6: Preparation of 2-chloro-5-(pentamylaminomethyl)benzoic acid

Methyl 2-chloro-5-(p-amylaminomethyl)benzoate (2.00 g, 7.05 mmol) in THF:MeOH:H ₂ O (3:2:1; 6 mL) and EtOAc The title compound was prepared following the procedure described in Step 3 of Intermediate 2 to afford 1.8 g of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): 12.3 (br s, 1H), 8.14 (brt, 1H), 7.61 (s, 1H), 7.47-7.44 (d, J = 8.1 Hz, 1H), 7.34 -7.32 (d, J = 7.8 Hz, 1H), 4.22 (d, J = 6.0 Hz, 2H), 1.18 (s, 9H).

Intermediate 6

1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine

Step 1: Preparation of 5-nitro-1-(3-(trifluoromethyl)phenoxy)isoquinoline

Solution of 1-chloro-5-nitro-isoquinoline (Step 1, Intermediate 1,200 mg, 0.96 mmol) was added in CH (2 mL) in ₃ CN solution of 3- (trifluoromethyl) phenol (233 Mg, 1.4 mmol) and K ₂ CO ₃ (265 mg, 1.92 mmol). The reaction mass was heated under reflux for 5 hours and diluted with water and extracted with chloroform. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 1.2 g. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.82 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.17 (s, 2H), 7.76 (t, J = 8.4 Hz, 1H), 7.61-7.47 (m, 4H); MS (m/z): 335.12 (M+H) ⁺ .

Step 2: Preparation of 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine

Use 5-nitro-1-(3-(trifluoromethyl)phenoxy)isoquinoline (200 mg, 0.59 mmol), iron powder (267 mg, 4.7 mmol) and NH ₄ Cl (312 mg, The title compound was prepared according to the procedure described in Step 3 of Intermediate 1 to afford 170 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 7.79 (d, J = 5.7 Hz, 1H), 7.70-7.50 (m, 6H), 7.40 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.02 (br s, 2H).

Intermediate 7

N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Step 1: Preparation of 8-nitroquinazolin-4(3 H )-one

Heating 2-amino-3-nitrobenzoic acid (3.0 g, 16.48 mmol) and NH ₄ OAc (5.2 g, 83.87 mmol) in CH(OEt) ₃ (20 mL) at 150 ° C. Suspension for 24 hours. Followed by reaction was quenched with aqueous NaHCO ₃ at rt and the resulting precipitate was filtered and dried. Containing 2-3% MeOH of CHCl _3, was purified by column chromatography to give 1.8 g solid material of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 12.72 (br s, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.24 (s, 1H) ), 7.69-7.64 (t, J = 7.8 Hz, 1H); MS (m/z): 192.19 (M+H) ⁺ .

Step 2: Preparation of 4-chloro-8-nitroquinazoline

A suspension of 8-nitroquinazolin-4( 3H )-one (1.0 g, 5.23 mmol) and PCl ₅ (1.3 g, 6.24 mmol) in POCI ₃ (5 mL). The reaction mixture was then concentrated and the concentrate was diluted with Et ₂ O. The precipitated solid was filtered and dried to give 1.0 g of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 9.25 (s, 1H), 8.71 (d, J = 7.8 Hz, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.07-8.02 (t, J = 7.8 Hz, 1H).

Step 3: Preparation of 8-nitro- N- (3-(trifluoromethyl)phenyl)quinazolin-4-amine

Heating 4-chloro-8-nitroquinazoline (300 mg, 1.43 mmol) and 3-(trifluoromethyl)aniline (461 mg, 2.86 mmol) in ⁱ PrOH (1.5 mL) at 120 ° C. Solution in 2 hours. The reaction mixture was then concentrated and purified on by triturated in Et ₂ O to give 425 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 10.52 (br s, 1H), 8.88 (d, J = 7.8 Hz, 1H), 8.75 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H) ), 8.31 (s, 1H), 8.22 (d, J = 6.9 Hz, 1H), 7.87-7.81 (t, J = 8.4 Hz, 1H), 7.71-7.65 (t, J = 7.8 Hz, 1H), 7.56 -7.30 (d, J = 7.8 Hz, 1H); MS (m/z): 335.19 (M+H) ⁺ .

Step 4: Preparation of N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

To 8-nitro- N- (3-(trifluoromethyl)phenyl)quinazolin-4-amine (500 mg, 1.49 mmol) and iron powder (834 mg, 14.9 mmol) in EtOH (10 mL) in the suspension was added _{NH 4 Cl (649 mg, 11.92} mmol) (3 mL) and the solution was heated under reflux in an aqueous reaction mixture for 2 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the concentrate was dissolved in CHCl _3. The organic layer was washed with _saturated aqueous NaHCO and brine. Dry, filter and concentrate the organic layer to give 350 mg title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 9.74 (br s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.45-7.42 (d, J = 7.5 Hz, 1H), 7.37-7.32 (t, J = 8.0 Hz, 1H), 7.00-6.98 (d, J = 7.8 Hz, 1H), 5.91 ( Br s, 2H); MS (m/z): 305.27 (M+H) ⁺ .

Intermediate 8

4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine

Step 1: Preparation of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinazoline

Add NaH (179 mg, 4.48 mmol, 60% in mineral oil) to a solution of 3-(trifluoromethyl)phenol (726 mg, 4.48 mmol) in THF (2 mL) The mixture was allowed to stand for 15 minutes. Then a solution of 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 470 mg, 2.24 mmol) in THF (3 mL) was added to the reaction mixture and stirred at room temperature. The reaction mixture was carried out for 4 hours. The reaction mixture was then quenched with EtOAc (EtOAc)EtOAc. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.88 (s, 1H), 8.68 (d, J = 7.8 Hz, 1H), 8.60 (d, J = 7.2 Hz, 1H), 7.99-7.94 (t, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.77 (s, 3H); MS (m/z): 336.12 (M+H) ⁺ .

Step 2: Preparation of 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine

Add 10% Pd/C (200 mg) to a solution of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinazoline (400 mg, 1.19 mmol) in EtOAc (5 mL) The suspension was hydrogenated at 20 psi for 1 hour in a Parr apparatus. The reaction mixture was then filtered through celite and concentrated. Use of CHCl ₃ containing 5% EtOAc, by residue was purified by column chromatography to give 300 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.60 (s, 1H), 7.79 (s, 1H), 7.75-7.71 (m, 3H), 7.47-7.44 (m, 2H), 7.11 (d, J = 6.3 Hz, 1H), 6.07 (s, 2H); MS (m/z): 305.19 (M+H) ⁺ .

Intermediate 9

N ⁴ -(4,4-difluorocyclohexyl)quinazoline-4,8-diamine

Step 1: Preparation of N- (4,4-difluorocyclohexyl)-8-nitroquinazolin-4-amine

Heating 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 200 mg, 0.954 mmol), 4,4-difluorocyclohexylamine (491 mg, 2.86 mmol) at 80 ° C in a sealed tube And a solution of DIPEA (367 mg, 2.86 mmol) in ⁱ PrOH (2 mL) for 2 h. The reaction mixture was then quenched with water and extracted with CHCl ₃ at room temperature. The organic layer was separated, dried, filtered and concentrated. Containing the ₃ CHCl 3-5% EtOAc, by concentrate was purified by column chromatography to give 180 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.59 - 8.55 (m, 2H), 8.43 - 8.40 (d, J = 7.2 Hz, 1H), 8.27 - 8.25 (d, J = 7.8 Hz, 1H), 7.69-7.63 (t, J = 7.8 Hz, 1H), 4.41 (m, 1H), 2.26-2.00 (m, 6H), 1.75-1.71 (m, 2H); MS (m/z): 309.18 (M+ H) ⁺ .

Step 2: Preparation of N ⁴ -(4,4-difluorocyclohexyl)quinazoline-4,8-diamine

Add iron powder (163 mg, 2.92) to a solution of N- (4,4-difluorocyclohexyl)-8-nitroquinazolin-4-amine (90 mg, 0.292 mmol) in EtOH (2 mL) mmol) and _{NH 4 Cl (127 mg, 2.33} mmol) and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was then filtered through celite. The diatomaceous earth bed was washed with CHCl ₃ containing 10% MeOH. The filtrate was washed with water and saturated _aqueous NaHCO. The organic layer was separated, dried, filtered and concentrated to give &lt ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.38 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.19-7.14 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.71 (s, 2H), 4.38 (m, 1H), 2.09-1.97 (m, 6H), 1.73-1.69 (m, 2H) MS (m/z): 279.12 (M+H) ⁺ .

Intermediate 10

4-((4,4-dimethylcyclohexyl)oxy)quinazoline-8-amine

Step 1: Preparation of 4-((4,4-dimethylcyclohexyl)oxy)-8-nitroquinazoline

To a solution of 4,4-dimethylcyclohexanol (140 mg, 1.097 mmol) in THF (2 mL), NaH (43 mg, 1.97 mmol, 60% in mineral oil). The reaction mixture was then stirred at the temperature for 20 minutes and 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 115 mg, 0.549 mmol) was added to the mixture. The reaction mixture was then stirred at 0-5 ° C for 4 hours and then at room temperature for 12 hours. The reaction mixture was then quenched with water and extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography using chloroform to afford 80 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.89 (s, 1H), 8.49 - 8.46 (d, J = 7.8 Hz, 1H), 8.45-8.42 (d, J = 7.8 Hz, 1H), 7.86- 7.80 (t, J = 8.4 Hz, 1H), 5.41 (m, 1H), 1.94 (m, 2H), 1.82-1.79 (m, 2H), 1.54 (m, 2H), 1.37-1.34 (m, 2H) , 0.99 (s, 3H), 0.67 (s, 3H); MS (m/z): 301.93 (M+H) ⁺ .

Step 2: Preparation of 4-((4,4-dimethylcyclohexyl)oxy)quinazoline-8-amine

Use 4-((4,4-dimethylcyclohexyl)oxy)-8-nitroquinazoline (80 mg, 0.265 mmol), NH ₄ Cl (114 mg, 2.216 mmol) and iron powder (148) The title compound was prepared according to the procedure described in Step 2 to give 53 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.63 (s, 1H), 7.34-7.30 (t, J = 7.8 Hz, 1H), 7.23-7.20 (d, J = 7.8 Hz, 1H), 7.01 6.99 (d, J = 8.4 Hz, 1H), 5.92 (s, 2H), 5.32 (m, 1H), 1.92 (m, 2H), 1.77-1.74 (m, 2H), 1.49 (m, 2H), 1.36 (m, 2H), 0.98 (s, 3H), 0.96 (s, 3H); MS (m/z): 271.99 (M+H) ⁺ .

Intermediate 11

4-(3-(trifluoromethyl)phenoxy)quinoline-8-amine

Step 1: Preparation of 4-chloroquinoline

Mixture of 4-quinolinol (1.0 g, 6.88 mmol) at reflux in POCl _{3 (3} mL) in the solution for 2 hours. The reaction mixture was then concentrated and the concentrate was dissolved in EtOAc. The organic layer was washed with a saturated NaHCO ₃ solution and water. The organic layer was separated, dried, filtered and concentrated to give &lt ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.87 (d, J = 4.5 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.14 - 8.11 (d, J = 8.7 Hz, 1H) , 7.93-7.88 (t, J = 7.5 Hz, 1H), 7.82-7.77 (m, 2H).

Step 2: Preparation of 4-chloro-8-nitroquinoline

In concentrated H ₂ SO ₄ (4.5 mL) of the solution at 0 ℃ wise a solution of 4-chloro-quinoline (1.0 g, 6.13 mmol) was added dropwise conc. HNO ₃ (1.8 mL) and the reaction mixture was stirred at 0-15 deg.] C 3 hours. Followed by the addition of aqueous NH ₄ OH at 0 ℃ and the reaction mixture was quenched by adjusting the pH value of the reaction mixture to 8. The solid precipitate was filtered and the filter cake was further purified by column chromatography to yield 900 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.98 (d, J = 5.1 Hz, 1H), 8.50-8.47 (d, J = 9.0 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H) , 8.02-7.99 (d, J = 4.8 Hz, 1H), 7.96-7.90 (t, J = 7.8 Hz, 1H).

Step 3: Preparation of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinoline

Heating 4-chloro-8-nitroquinoline (200 mg, 0.96 mmol), 3-(trifluoromethyl)phenol (250 mg, 1.54 mmol), K ₂ CO ₃ (414) at 100 ° C in a sealed tube mg, 2.99 mmol) in CH ₃ CN (2 mL) in a suspension of 8 hours. The reaction mixture was then quenched with water and EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 120 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.83 (d, J = 5.4 Hz, 1H), 8.60-8.57 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 6.9 Hz, 1H) , 7.85-7.73 (m, 5H), 6.87 (d, J = 5.4 Hz, 1H).

Step 4: Preparation of 4-(3-(trifluoromethyl)phenoxy)quinoline-8-amine

a suspension of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinoline (200 mg, 0.60 mmol) and iron powder (267 mg, 4.77 mmol) in EtOH (3 mL) was added _{NH 4 Cl (312 mg, 5.89} mmol) in the solution and heated at reflux in water (2 mL) the reaction mixture for 2 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the concentrate was dissolved in CHCl _3. The organic layer was washed with _saturated aqueous NaHCO and brine. The organic layer was separated, dried, filtered and evaporated elut ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.58 (d, J = 4.8 Hz, 1H), 7.77-7.65 (m, 3H), 7.55 (d, J = 7.8 Hz, 1H), 7.32 (m, 2H), 6.64 (m, 1H), 6.71 (d, J = 4.8 Hz, 1H), 6.00 (br s, 2H); MS (m/z): 305.22 (M+H) ⁺ .

Intermediate 12

N ⁸ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine

Step 1: Preparation of ethyl 8-bromo-4-hydroxyquinoline-3-carboxylate

A solution of 2-bromoaniline (2.5 g, 14.62 mmol) and ethyl ethoxymethylenemalonate (3.16 g, 14.62 mmol) was heated at 100 °C for 3 hours. The volatiles were then removed by passing through a stream of nitrogen and the molten material was slowly added to boiling diphenyl ether (10 mL) and the mixture was heated under reflux for 2 h. Petroleum ether was then added to the reaction mixture at room temperature and the precipitated solid was collected by filtration and dried to give 3.5 g of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 11.65 (br s, 1H), 8.45 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H) ), 7.39-7.34 (t, J = 7.8 Hz, 1H), 4.26-4.19 (q, J = 7.2, 14.1 Hz, 2H), 1.30-1.26 (t, J = 6.9 Hz, 3H).

Step 2: Preparation of ethyl 8-bromo-4-chloroquinoline-3-carboxylate

Heating bromo-4-hydroxy quinoline at 80 ℃ -3- carboxylic acid ethyl ester (2.0 g, 6.75 mmol) in POCl ₃ (10 mL) in the solution for 3 hours. The volatiles were then removed and ice water was added to the residue. The precipitated solid was filtered and dried to give 1.8 g of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 9.26 (s, 1H), 8.44 - 8.37 (m, 2H), 7.79 - 7.64 (t, J = 7.8 Hz, 1H), 4.48-4.43 (q, J = 7.2, 14.1 Hz, 2H), 1.41-1.36 (t, J = 6.9 Hz, 3H); MS (m/z): 314.01 (M+H) ⁺ .

Step 3: Preparation of ethyl 8-bromo-4-((4-methoxybenzyl)amino)quinoline-3-carboxylate

To a solution of 8-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (1.8 g, 5.72 mmol) in DMF (10 mL) EtOAc (EtOAc) 2.22 g, 17.21 mmol) and the reaction mixture was heated at 120 °C for 4 hours. The reaction mixture was then quenched with water and EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 1.2 g. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 9.11 (br s, 1H), 8.89 (s, 1H), 8.46-8.43 (d, J = 8.7 Hz, 1H), 8.12-8.09 (d, J = 7.8 Hz, 1H), 7.38-7.33 (t, J = 8.4 Hz, 1H), 7.27-7.24 (d, J = 8.4 Hz, 2H), 6.91-6.89 (d, J = 8.1 Hz, 2H), 8.17 ( d, 2H), 4.26-4.24 (q, J = 7.2, 14.1 Hz, 2H), 3.72 (s, 3H), 1.29-1.24 (t, J = 6.9 Hz, 3H).

Step 4: Preparation of 8-bromo-4-((4-methoxybenzyl)amino)quinoline-3-carboxylic acid

To ethyl 8-bromo-4-((4-methoxybenzyl)amino)quinoline-3-carboxylate (1.2 g, 2.89 mmol) in THF-MeOH-H ₂ O (10:7:3) LiOH-H ₂ O (452 mg, 10.77 mmol) was added to a solution in 20 mL) and the mixture was stirred at room temperature for 12 hr. The reaction mixture is then acidified with citric acid and the organic volatiles are removed. The residue was extracted with EtOAc. The organic layer was washed with brine, dried, dried, filtered and evaporated ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.96 (s, 1H), 8.42-8.39 (d, J = 8.7 Hz, 1H), 8.11-8.09 (d, J = 7.2 Hz, 1H), 7.35- 7.30 (m, 3H), 6.95-6.92 (d, J = 8.7 Hz, 2H), 4.91 (s, 2H), 3.74 (s, 3H).

Step 5: Preparation of 8-bromo- N- (4-methoxybenzyl)quinoline-4-amine

A solution of 8-bromo-4-((4-methoxybenzyl)amino)quinoline-3-carboxylic acid (1.0 g, 2.58 mmol) in diphenyl ether (5 mL) at 240 °C 30 minutes. Petroleum ether was then added to the reaction mixture at room temperature and the precipitated solid was filtered and dried to give the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.38 (d, J = 5.4 Hz, 1H), 8.34 - 8.31 (d, J = 9.0 Hz, 1H), 8.06 (t, 1H), 8.02-7.99 ( d, J = 7.5 Hz, 1H), 7.37-7.29 (m, 3H), 6.90-6.87 (d, J = 8.4 Hz, 2H), 6.44 (d, J = 5.1 Hz, 1H), 4.49 (d, J =6.0 Hz, 2H), 3.71 (s, 3H).

Step 6: Preparation of N ⁴ -(4-methoxybenzyl) -N ⁸ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine

Heating 8-bromo- N- (4-methoxybenzyl)quinolin-4-amine (300 mg, 0.874 mmol), m-trifluoroaniline (1.55 g, 9.63 mmol) in a microwave vial at 100 °C. , ginseng (diphenylmethyleneacetone) palladium (0) (16 mg, 0.017 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (32 mg, 0.051 mmol) and in the ^{NaO t Bu (109 mg, 1.14} mmol) in toluene (3 mL) solution for 30 minutes. Water was then added to the reaction mixture which was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give &lt ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.87 (s, 1H), 8.30 (d, J = 5.4 Hz, 1H), 7.86 (brt, 1H), 7.76-7.73 (d, J = 9.0 Hz , 1H), 7.67 (m, 2H), 7.45 (m, 2H), 7.37-7.30 (m, 3H), 7.20 (d, J = 6.6 Hz, 1H), 6.91-6.88 (d, J = 8.1 Hz, 2H), 6.42 (d, J = 5.4 Hz, 1H), 4.48 (d, 2H), 3.71 (s, 3H).

Step 7: Preparation of N ⁸ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine

Stirring N ⁴ -(4-methoxybenzyl)- N ⁸ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine (180 mg, 0.425 mmol) at 80 ° The solution in TFA (2 mL) was 2 hours. NaHCO ₃ solution followed by saturated reaction mixture was quenched and extracted with EtOAc. The organic layer was washed with water and brine, dried, filtered and concentrated. The residue was triturated with Et ₂ O to give 120 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.86 (s, 1H), 8.30 (d, J = 4.5 Hz, 1H), 7.66-7.43 (m, 4H), 7.38 (t, J = 7.8 Hz, 1H), 7.21-7.18 (d, J = 7.8 Hz, 1H), 6.83 (m, 3H), 6.60 (d, J = 5.1 Hz, 1H).

Intermediate 13

4-nitro-5-(pentamylaminomethyl)benzoic acid 4-nitrophenyl ester

Add EDCl (210 mg, 1.09 mmol) to a solution of 2-chloro-5-(p-amylaminomethyl)benzoic acid (5,300 mg, 1.12 mmol) in THF (5 mL) Nitrophenol (154 mg, 1.10 mmol) and DIPEA (558 mg, 4.39 mmol). Water was then added to the reaction mixture which was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 222 g ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.36 (d, J = 9.0 Hz, 2H), 8.20 (t, 1H), 7.97 (s, 1H), 7.62-7.59 (m, 3H), 7.51 ( d, J = 8.1 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 1.11 (s, 9H).

Intermediate 14

N ⁴ -(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Step 1: Preparation of N- (2-fluoro-5-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine

Heating 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 150 mg, 0.72 mmol) and 2-fluoro-5-(trifluoromethyl)aniline (387 mg, 2.16 mmol) at 50 °C A solution in THF (4 mL) for 2 h. Water was then added to the reaction mixture which was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 250 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 10.46 (s, 1H), 8.74 - 8.71 (d, J = 8.7 Hz, 1H), 8.63 (s, 1H), 8.43 - 8.40 (d, J = 7.2 Hz, 1H), 8.01 (d, 1H), 7.86-7.81 (m, 2H), 7.66-7.63 (t, J = 9.3 Hz, 1H); MS[M+H] ⁺ : 353.14.

Step 2: Preparation of N ⁴ -(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Use N- (2-fluoro-5-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine (250 mg, 0.71 mmol), NH ₄ Cl (304 mg, 5.68 mmol) The title compound was prepared according to the procedure described in Step 2 to give 100 mg of the title product, EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 9.71 (s, 1H), 8.44 (s, 1H), 7.78 (d, 1H), 7.70 (m, 1H), 7.60-7.57 (t, J = 9.6 Hz, 1H), 7.50-7.47 (d, J = 8.4 Hz, 1H), 7.36-7.30 (t, J = 7.8 Hz, 1H), 6.99-6.97 (d, J = 7.8 Hz, 1H), 5.89 (s , 2H); MS [M+H] ⁺ : 323.29.

Intermediate 15

N ⁴ -(4,4-dimethylcyclohexyl)quinazoline-4,8-diamine

Step 1: Preparation of N- (4,4-dimethylcyclohexyl)-8-nitroquinazolin-4-amine

4-chloro-8-nitro-quinazoline (Intermediate 7, Step 2,150 mg, 0.72 mmol) was added in CH _{K 2 CO 3 (300 mg,} 2.15 mmol) (3 mL) in a solution of ₃ CN in And 4,4-dimethylcyclohexylamine hydrochloride (352 mg, 2.15 mmol) and the reaction mixture was heated under reflux for 3 h. Water was then added to the reaction mixture which was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 150 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.58-8.55 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 8.38-8.35 (d, J = 7.2 Hz, 1H), 8.25- 8.22 (d, J = 7.8 Hz, 1H), 7.67-7.61 (t, J = 7.8 Hz, 1H), 4.17 (m, 1H), 1.75-1.56 (m, 4H), 1.46-1.18 (m, 4H) , 0.98 (s, 3H), 0.95 (s, 3H); MS [M+H] ⁺ : 301.20.

Step 2: Preparation of N ⁴ -(4,4-dimethylcyclohexyl)quinazoline-4,8-diamine

Using N- (4,4-dimethylcyclohexyl)-8-nitroquinazolin-4-amine (210 mg, 0.69 mmol), NH ₄ Cl (295 mg, 5.52 mmol) and iron powder (386 The title compound was obtained after the title compound was obtained from EtOAc (EtOAc: EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.32 (s, 1H), 7.57-7.55 (d, J = 6.6 Hz, 1H), 7.33-7.29 (d, J = 8.4 Hz, 1H), 7.13 7.11 (t, J = 7.8 Hz, 1H), 6.84-6.82 (d, J = 7.2 Hz, 1H), 5.66 (s, 2H), 4.08 (m, 1H), 1.69-1.60 (m, 4H), 1.38 -1.28 (m, 4H), 0.95 (s, 3H), 0.92 (s, 3H).

Intermediate 16

4-Chloro-2-fluoro-3-((4-((3-(trifluoromethyl)phenyl))amino)quinazolin-8-yl)aminecarboxamido)benzylaminocarbamic acid Tributyl ester

Using N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 7,87 mg, 0.285 mmol), 3-(((t-butoxycarbonyl) Amino)methyl)-6-chloro-2-fluorobenzoic acid (130 mg, 0.428 mmol), ethylene dichloride (81 mg, 0.64 mmol), DMF (1 drop) and DIPEA (111 mg, 0.86 mmol) ) of _{CH 2 Cl 2 (4 mL)} , the title compound was prepared by following the procedures described in example 1 to give 80 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.66 (s, 1H), 10.14 (s, 1H), 8.82 (d, 1H), 8.71 (s, 1H), 8.36 (m, 2H), 8.23 (d, 1H), 7.73 (t, 1H), 7.66 (t, 1H), 7.51 (m, 2H), 7.42 (m, 2H), 4.18 (d, 2H), 1.40 (s, 9H); M+H] ⁺ : 590.08.

Intermediate 17

N ⁴ -(4-fluoro-3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Step 1: Preparation of N- (4-fluoro-3-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine

Stir 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 200 mg, 0.95 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (510 mg, 2.85 mmol) at rt. A solution in THF (4 mL) for 2 h. Water was then added to the reaction mixture which was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 250 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 10.47 (s, 1H), 8.83-8.80 (d, J = 8.4 Hz, 1H), 8.72 (s, 1H), 8.42-8.39 (d, J = 7.8 Hz, 1H), 8.31-8.25 (m, 2H), 7.86-7.81 (t, J = 7.8 Hz, 1H), 7.64 - 7.58 (t, J = 9.6 Hz, 1H).

Step 2: Preparation of N ⁴ -(4-fluoro-3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Use N- (4-fluoro-3-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine (250 mg, 0.71 mmol), NH ₄ Cl (304 mg, 5.68 mmol) The title compound was prepared according to the procedure described in Step 2 to give the title compound (yield: EtOAc, EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 9.75 (s, 1H), 8.56 (s, 1H), 8.35 (m, 1H), 8.27 (m, 1H), 7.60-7.51 (m, 2H), 7.37-7.32 (t, J = 7.5 Hz, 1H), 7.00-6.98 (d, J = 7.5 Hz, 1H), 5.91 (s, 2H).

Intermediate 18

8-Nitro-4-(((1 s ,4 s )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline

Intermediate 19

8-Nitro-4-(((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline

Use 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 500 mg, 2.39 mmol) and 4-(Trifluoromethyl)cyclohexanol (cis and trans mixture) (803 mg , 4.78 mmol) and NaH (191 mg, 4.78 mmol, 60% in mineral oil) in THF (10 mL). 301 mg intermediate 19. Intermediate 18: ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.91 (s, 1H), 8.51 - 8.45 (t, J = 8.4 Hz, 2H), 7.89-7.84 (t, J = 7.8 Hz, 1H), 5.66 (m, 1H), 3.83 (m, 1H), 2.22-2.18 (m, 2H), 1.81-1.61 (m, 6H); Intermediate 19: ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.92 (s, 1H), 8.50-8.48 (d, J = 7.8 Hz, 1H), 8.41-8.38 (d, J = 7.8 Hz, 1H), 7.85-7.80 (t, J = 8.4 Hz, 1H) ), 5.38-5.31 (m, 1H), 2.28 (m, 2H), 2.02-1.98 (m, 3H), 1.68-1.57 (m, 4H); MS[M+H] ⁺ : 341.98.

Intermediate 20

4-(((1 s , 4 s )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline-8-amine

Using 8-nitro-4-(((1 s , 4 s )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline (intermediate 18, 150 mg, 0.44 mmol), NH ₄ Cl (188 mg, 3.52 mmol) and iron powder (246 mg, 4.40 mmol) in EtOH (2 mL) and water (1 mL). Title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.63 (s, 1H), 7.37-7.32 (t, J = 7.8 Hz, 1H), 7.22-7.19 (d, J = 7.8 Hz, 1H), 7.01 -6.98 (d, J = 7.5 Hz, 1H), 5.93 (s, 2H), 5.57 (m, 1H), 2.15-2.11 (m, 3H), 1.79-1.75 (m, 6H); MS [M+H ] ⁺ :312.07.

Intermediate 21

4-(((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline-8-amine

Using 8-nitro-4-(((1 r , 4 r )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline (intermediate 19, 250 mg, 0.733 mmol), NH ₄ Cl (313 mg, 5.865 mmol) and iron powder (410 mg, 7.33 mmol) in EtOH (5 mL) and water (2 mL), the title compound Title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.65 (s, 1H), 7.34 - 7.29 (t, J = 7.8 Hz, 1H), 7.18-7.16 (d, J = 7.8 Hz, 1H), 7.01 -6.99 (d, J = 7.5 Hz, 1H), 5.94 (s, 2H), 5.25 (m, 1H), 2.49 (m, 1H), 2.25 (m, 2H), 2.00-1.97 (m, 2H), 1.62-1.55 (m, 4H); MS [M+H] ⁺ : 312.10.

Intermediate 22

4-(2-Fluoro-5-(trifluoromethyl)phenoxy)quinazolin-8-amine

Step 1: Preparation of 4-(2-fluoro-5-(trifluoromethyl)phenoxy)-8-nitroquinazoline

Using 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 300 mg, 1.43 mmol), 2-fluoro-5-(trifluoromethyl)phenol (309 mg, 1.72 mmol) and NaH (69 mg, 1.72 mmol, 60% in mineral oil) THF (5 mL). ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.93 (s, 1H), 8.72-8.69 (d, J = 8.1 Hz, 1H), 8.66-8.64 (d, J = 7.8 Hz, 1H), 8.15- 8.13 (d, J = 4.8 Hz, 1H), 8.03-7.98 (t, J = 8.1 Hz, 1H), 7.86 (m, 1H), 7.80-7.74 (t, J = 9.6 Hz, 1H).

Step 2: Preparation of 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinazolin-8-amine

Use 4-(2-fluoro-5-(trifluoromethyl)phenoxy)-8-nitroquinazoline (500 mg, 1.42 mmol), NH ₄ Cl (760 mg, 14.2 mmol) and iron powder (239 mg, 4.26 mmol) <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.60 (s, 1H), 8.06-8.04 (d, J = 5.1 Hz, 1H), 7.79 (m, 1H), 7.69-7.67 (t, J = 9.0 Hz, 1H), 7.50-7.40 (m, 2H), 7.13-7.10 (d, J = 7.2 Hz, 1H), 6.12 (br s, 2H).

Intermediate 23

N ⁴ -(2-fluoro-4-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Step 1: Preparation of N- (2-fluoro-4-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine

Using THF containing 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 300 mg, 1.43 mmol) and 2-fluoro-4-(trifluoromethyl)aniline (512 mg, 2.86 mmol) The title compound was prepared (10 mL), m. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.84-8.81 (d, J = 9.0 Hz, 1H), 8.59 (s, 1H), 8.44 - 8.42 (d, J = 7.8 Hz, 1H), 7.84 7.82 (m, 4H), 7.69-7.66 (d, J = 7.8 Hz, 1H).

Step 2: Preparation of N ⁴ -(2-fluoro-4-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Using N- (2-fluoro-4-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine (275 mg, 0.78 mmol), NH ₄ Cl (418 mg, 7.80 mmol) The title compound was prepared according to the procedure described in Step 2 to give 220 mg of the title product, EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.74 (s, 1H), 8.43 (s, 1H), 7.84 - 7.76 (m, 2H), 7.64 - 7.62 (d, J = 7.8 Hz, 1H) , 7.52-7.49 (d, J = 8.1 Hz, 1H), 7.32 (t, 1H), 6.99-6.96 (d, J = 7.2 Hz, 1H), 5.88 (br s, 2H).

Intermediate 24

N ⁴ -(6-(trifluoromethyl)pyridin-3-yl)quinazoline-4,8-diamine

Step 1: Preparation of 8-nitro- N- (6-(trifluoromethyl)pyridin-3-yl)quinazolin-4-amine

Using THF containing 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 250 mg, 1.19 mmol) and 6-(trifluoromethyl)pyridin-3-amine (386 mg, 2.38 mmol) The title compound was prepared (5 mL ¹ H NMR (300 MHz, DMSO d ₆ ): δ 10.60 (s, 1H), 9.21. (s, 1H), 8.85-8.82 (d, J = 8.7 Hz, 1H), 8.79 (s, 1H), 8.65- 8.63 (d, J = 8.7 Hz, 1H), 8.44 - 8.42 (d, J = 7.2 Hz, 1H), 7.99-7.96 (d, J = 9.0 Hz, 1H), 7.89-7.87 (t, J = 7.8 Hz) , 1H).

Step 2: Preparation of N ⁴ -(6-(trifluoromethyl)pyridin-3-yl)quinazoline-4,8-diamine

Containing 8-nitro - N - (6- (trifluoromethyl) pyridin-3-yl) quinazolin-4-amine (400 mg, 1.19 mmol), NH 4 Cl (637 mg, 11.90 mmol) and Iron powder (200 mg, 3.57 mmol) in EtOAc (5 mL) EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.97 (s, 1H), 9.22 (s, 1H), 8.69-8.67 (d, J = 7.2 Hz, 1H), 8.61 (s, 1H), 7.93 -7.89 (d, J = 8.1 Hz, 1H), 7.63-7.60 (d, J = 7.8 Hz, 1H), 7.37 (t, 1H), 7.01-6.99 (d, J = 7.2 Hz, 1H), 5.95 ( Br s, 2H).

Intermediate 25

N ⁴ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine

Step 1: Preparation of 8-nitro- N- (3-(trifluoromethyl)phenyl)quinolin-4-amine

Heating 4-chloro-8-nitroquinoline (step 2, intermediate 11, 100 mg, 0.48 mmol) and 3-(trifluoromethyl)aniline (309 mg, 1.92 mmol) in a microwave at 150 °C The mixture was allowed to stand for 20 minutes. Then water was added and the mixture was extracted with CHCl ₃ to the reaction. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 250 mg of title product.

Step 2: Preparation of N ⁴ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine

Use 8-nitro- N- (3-(trifluoromethyl)phenyl)quinolin-4-amine (250 mg, 0.75 mmol), NH ₄ Cl (321 mg, 6.00 mmol) and iron powder (420) The title compound was prepared in EtOAc (3 mL) elute

Intermediate 26

N ⁴ -(4,4-dimethylcyclohexyl)-2-(trifluoromethyl)quinazoline-4,8-diamine

Step 1: Preparation of 2-amino-3-nitrobenzamide

Add BOP (18.21 g, 41.21 mmol), NH ₄ Cl (4.41 g, 82.41 mmol) to a solution of 2-amino-3-nitrobenzoic acid (5.00 g, 27.47 mmol) in DMSO (30 mL) DIPEA (10.63 g, 82.41 mmol) and the reaction mixture was stirred at room temperature for 14 hours and it was quenched with ice-water and the resulting precipitate was filtered, washed with ₂ O Et and dried to give 4.90 g of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.48 (br s, 2H), 8.19-8.17 (m, 2H), 7.96-7.94 (d, J = 7.2 Hz, 1H), 7.62 (br s, 1H) ), 6.71-6.65 (t, J = 7.8 Hz, 1H).

Step 2: Preparation of 8-nitro-2-(trifluoromethyl)quinazolin-4(3 H )-one

A solution of 2-amino-3-nitrobenzamide (1.0 g, 5.52 mmol) in trifluoroacetic anhydride (5 mL) was heated at 100 ° C for 4h. The reaction mixture was then quenched with water and filtered and dried to give &lt ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.43-8.40 (d, J = 7.8 Hz, 2H), 7.85-7.80 (t, J = 7.8 Hz, 1H); MS (m/z): 258.26 ( MH) ⁺ .

Step 3: Preparation of 4-chloro-8-nitro-2-(trifluoromethyl)quinazoline

POCl ₃ (2.5 mL) containing 8-nitro-2-(trifluoromethyl)quinazolin-4( 3H )-one (500 mg, 1.93 mmol) and PCl ₅ (477 mg, 2.32 mmol) The title compound was prepared following the procedure of Intermediate 7, Step 2 to give 1.0 g of the title product.

Step 4: Preparation of N- (4,4-dimethylcyclohexyl)-8-nitro-2-(trifluoromethyl)quinazolin-4-amine

Heating 4-chloro-8-nitro-2-(trifluoromethyl)quinazoline (200 mg, 0.72 mmol), 4,4-dimethylcyclohexylamine (109 mg, 0.86 mmol), in _{CH 3 CN K 2 CO 3 (} 398 mg, 2.89 mmol) (2 mL) in a suspension of 8 hours. The reaction mixture was then quenched with water and EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 120 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.91-8.89 (d, J = 7.2 Hz, 1H), 8.69-8.66 (d, J = 7.8 Hz, 1H), 8.39-8.37 (d, J = 7.8 Hz, 1H), 7.84-7.79 (t, J = 8.1 Hz, 1H), 4.12 (m, 1H), 1.76-1.64 (m, 4H), 1.46-1.28 (m, 4H), 0.98 (s, 3H) , 0.95 (s, 3H).

Step 5: Preparation of N ⁴ -(4,4-dimethylcyclohexyl)-2-(trifluoromethyl)quinazoline-4,8-diamine

Using N- (4,4-dimethylcyclohexyl)-8-nitro-2-(trifluoromethyl)quinazolin-4-amine (200 mg, 0.54 mmol), NH ₄ Cl (115 mg The title compound was prepared according to the procedure described in Step 2 to give 120 mg of the titled product, EtOAc (EtOAc: EtOAc: EtOAc: ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.11-8.08 (d, J = 8.1 Hz, 1H), 7.45-7.42 (d, J = 8.4 Hz, 1H), 7.34-7.29 (t, J = 7.8 Hz, 1H), 6.99-6.69 (d, J = 7.2 Hz, 1H), 5.81 (br s, 2H), 4.07 (m, 1H), 1.76-1.62 (m, 4H), 1.44-1.22 (m, 4H), 0.97 (s, 3H), 0.94 (s, 3H).

Intermediate 27

2-methyl- N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Step 1: Preparation of 2-methyl-8-nitroquinazolin-4(3 H )-one

Heating 2-amino-3-nitrobenzoic acid (500 mg, 2.75 mmol) in Ac ₂ O (3.5 mL) in the solution for 1 hour under reflux. The reaction mixture was then concentrated and the residue was triturated with Et ₂ O. The resulting precipitate was filtered and dried. The solid material was then dissolved in aqueous NH ₃ solution (10 mL) and the solution was heated for 2 hours under reflux. The reaction mixture was then concentrated and the residue was triturated with Et ₂ O. The resulting precipitate was filtered and dried to give 250 mg of the title product. ^{1 H NMR (300 MHz, DMSO-} d 6): δ 12.62 (br s, 1H), 8.31-8.28 (d, J = 8.4 Hz, 1H), 8.24-8.21 (d, J = 7.8 Hz, 1H), 7.61-7.56 (t, J = 7.8 Hz, 1H), 2.36 (s, 3H).

Step 2: Preparation of 4-chloro-2-methyl-8-nitroquinazoline

Add POCl ₃ (374 mg, 2.44 mmol) to a solution of 2-methyl-8-nitroquinazolin-4( 3H )-one (250 mg, 1.22 mmol) in toluene (1 mL) The reaction mixture was heated under reflux for 10 hours. The reaction mixture was then concentrated and triturated with Et ₂ O. The resulting precipitate was filtered and dried to give 150 mg title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.60-8.58 (d, J = 7.8 Hz, 1H), 8.52-8.49 (d, J = 9.0 Hz, 1H), 7.95-7.89 (t, J = 7.8 Hz, 1H), 2.75 (s, 3H).

Step 3: Preparation of 2-methyl-8-nitro- N- (3-(trifluoromethyl)phenyl)quinazolin-4-amine

Use 4-chloro-2-methyl-8-nitroquinazoline (150 mg, 0.671 mmol) and 3-(trifluoromethyl)aniline (324 mg, 2.01 mmol) in THF (5 mL). The title compound was prepared by the procedure described in Step 1 to give 150 mg of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 8.78-8.75 (d, J = 8.7 Hz, 1H), 8.36 (s, 1H), 8.32-8.29 (d, J = 7.5 Hz, 1H), 8.27-8.24 (d, J = 9.3 Hz, 1H), 7.74-7.62 (m, 2H), 7.50-7.48 (d, J = 8.7 Hz, 1H), 2.52 (s, 3H).

Step 4: Preparation of 2-methyl- N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Using 2- methyl-8-nitro - N - (3- (trifluoromethyl) phenyl) quinazolin-4-amine (150 mg, 0.43 mmol), NH 4 Cl (184 mg, 3.44 mmol And the iron powder (241 mg, 4.31 mmol) in EtOH (5 mL) and water (1 mL). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.66 (s, 1H), 8.47 (s, 1H), 8.32-8.29 (d, J = 7.8 Hz, 1H), 7.61 (m, 2H), 7.42 -7.40 (d, J = 7.2 Hz, 1H), 7.29-7.24 (t, J = 7.2 Hz, 1H), 6.96-6.94 (d, J = 7.5 Hz, 1H), 5.79 (br s, 2H), 2.55 (s, 3H).

Intermediate 28

1-((4,4-dimethylcyclohexyl)oxy)isoquinolin-5-amine

Step 1: Preparation of 1-((4,4-dimethylcyclohexyl)oxy)-5-nitroisoquinoline

Use 1-chloro-5-nitroisoquinoline (Intermediate 1, Step 1, 200 mg, 0.96 mmol) and 4,4-Dimethylcyclohexanol (135 mg, 1.05 mmol) and NaH (42 mg) The title compound was prepared according to the procedure described in Step 1 to give 180 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.65 (d, J = 7.8 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 6.6 Hz, 1H), 7.94 (d, J = 6.3 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 5.33 (m, 1H), 2.04-1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.43 - 1.39 (m, 4H), 1.02 (s, 3H), 0.99 (s, 3H).

Step 2: Preparation of 1-((4,4-dimethylcyclohexyl)oxy)isoquinolin-5-amine

Use 1-((4,4-dimethylcyclohexyl)oxy)-5-nitroisoquinoline (95 mg, 0.32 mmol), NH ₄ Cl (170 mg, 3.16 mmol) and iron powder (48) The title compound was obtained after the title compound was obtained from EtOAc (EtOAc: EtOAc) ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.95 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 5.28 (m, 1H), 2.04-1.94 (m, 2H), 1.82 (m, 2H), 1.41-1.37 (m, 4H), 1.01 (s, 3H), 0.97 (s, 3H).

Intermediate 29

N ¹ -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)isoquinoline-1,5-diamine

Step 1: Preparation of 5-nitro- N -((1 r , 4 r )-4-(trifluoromethyl)cyclohexyl)isoquinolin-1-amine

1-Chloro-5-nitroisoquinoline (Intermediate 1, Step 1, 250 mg, 1.20 mmol), K ₂ CO ₃ (105 mg, 1.44 mmol) and (1 r , 4 r )-4-( The title compound was prepared following the procedure described in Step 1 to give 150 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.74 (d, J = 8.7 Hz, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 6.3 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7, 26 (d, J = 5.7 Hz, 1H), 4.12 (m, 1H), 2.31 (m, 1H) ), 2.10 (m, 2H), 1.98 (m, 2H), 1.44 (m, 4H).

Step 2: Preparation of N ¹ -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)isoquinoline-1,5-diamine

Use 5-nitro- N -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)isoquinolin-1-amine (150 mg, 0.44 mmol), NH ₄ Cl (239 mg The title compound was prepared according to the procedure described in Step 2 to give 60 mg of the title product, EtOAc (EtOAc: EtOAc:

Intermediate 30

N ⁴ -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)quinazoline-4,8-diamine

Step 1: Preparation of 8-nitro- N -((1 r , 4 r )-4-(trifluoromethyl)cyclohexyl)quinazolin-4-amine

4-Chloro-8-nitroquinazoline (Intermediate 7, Step 2, 150 mg, 0.72 mmol), K ₂ CO ₃ (198 mg, 1.43 mmol) and (1 r , 4 r ) -4- ( The title compound was prepared following the procedure described in Step 1 to give the title compound. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.60 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.44 (d, J = 7.5 Hz, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 4.16 (m, 1H), 2.34 (m, 1H), 2.06 (m, 2H), 1.98-1.94 (m, 2H), 1.52- 1.40 (m, 4H).

Step 2: Preparation of N ⁴ -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)quinazoline-4,8-diamine

Use 8-nitro- N -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)quinazolin-4-amine (200 mg, 0.59 mmol), NH ₄ Cl (249 mg) The title compound was prepared according to the procedure described in Step 2 to give 150 mg of the title product. EtOAc (EtOAc: EtOAc: ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.36 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 5.69 (s, 2H), 4.16 (m, 1H), 2.28 (m, 1H), 2.03 (m, 2H), 1.96-1.93 ( m, 2H), 1.50-1.23 (m, 4H).

Intermediate 31

5-nitro-1-(((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinoline

Intermediate 32

5-nitro-1-(((1 s ,4 s )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinoline

Use 1-chloro-5-nitroisoquinoline (Intermediate 1, Step 1, 250 mg, 1.28 mmol) and 4-(Trifluoromethyl)cyclohexanol (cis and trans mixture) (324 mg , 1.93 mmol) and NaH (61 mg, 2.56 mmol, 60% in mineral oil) in THF (4 mL). 83 mg intermediate 32. Intermediate 31: ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.61 (d, J = 8.4 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 6.3 Hz , 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 5.30-5.27 (m, 1H), 2.41 (m, 2H), 2.11-2.09 (m, 3H), 1.68-1.56 (m, 4H).

Intermediate 32: ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.63 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 6.3 Hz , 1H), 7.98 (d, J = 6.3 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 5.65 (m, 1H), 2.34 - 2.29 (m, 2H), 1.86-1.82 (m, 3H), 1.75-1.70 (m, 4H).

Intermediate 33

1-(((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-5-amine

Use 5-nitro-1-(((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinoline (150 mg, 0.44 mmol), NH ₄ Cl (187 mg) The title compound was prepared according to the procedure described in Step 2 to give 130 mg of the title product. m. m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.81 (d, J = 6.3 Hz, 1H), 7.45 (d, J = 5.7 Hz, 1H), 7.29-7.20 (m, 2H), 6.82 (d) , J = 6.9 Hz, 1H), 5.82 (br s, 2H), 5.12 (m, 1H), 2.35 (m, 1H), 2.25-2.22 (m, 2H), 1.96-1.92 (m, 2H), 1.55 -1.43 (m, 4H).

Intermediate 34

1-(((1 s , 4 s )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-5-amine

Use 5-nitro-1-(((1 s ,4 s )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinoline (100 mg, 0.29 mmol), NH ₄ Cl (122 mg) The title compound was prepared according to the procedure described in Step 2 to give 70 mg of the title product. m. m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.82 (d, J = 6.6 Hz, 1H), 7.45 (d, J = 5.7 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 6.6 Hz, 1H), 5.83 (br s, 2H), 5.46 (s, 1H), 2.37 (m, 1H), 2.24 (m, 2H), 2.09 (m, 2H), 1.70-1.67 (m, 4H).

Intermediate 35

4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinoline-8-amine

Step 1: Preparation of 4-(2-fluoro-5-(trifluoromethyl)phenoxy)-8-nitroquinoline

Using 4-chloro-8-nitroquinoline (Intermediate 11, Step 2, 300 mg, 1.44 mmol), 2-fluoro-5-(trifluoromethyl)phenol (389 mg, 2.16 mmol), K _{2 CO 3 (596 mg, 4.32 mmol} ) of CH ₃ CN (4 mL), followed intermediate 11, the procedure described in step 3 to give the title compound was prepared 432 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.82 (d, J = 4.8 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.86-7.75 (m, 3H), 6.93 (d, J = 4.8 Hz, 1H); MS (m/z): 353.21. (M+H) ⁺ .

Step 2: Preparation of 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinoline-8-amine

Use 4-(2-fluoro-5-(trifluoromethyl)phenoxy)-8-nitroquinoline (432 mg, 1.22 mmol), iron powder (683 mg, 12.2 mmol) and NH ₄ Cl ( 517 mg, 9.76 mmol) of EtOAc (5 mL) EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.52 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 6.6 Hz, 1H), 7.79-7.70 (m, 2H), 7.35 (d, J = 6.0 Hz, 2H), 6.91 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 4.2 Hz, 1H), 5.98 (br s, 2H).

Intermediate 36

1-(2-fluoro-5-(trifluoromethyl)phenoxy)isoquinolin-5-amine

Step 1: Preparation of 1-(2-fluoro-5-(trifluoromethyl)phenoxy)-5-nitroisoquinoline

Use 1-chloro-5-nitroisoquinoline (Step 1, intermediate 1, 250 mg, 1.19 mmol), 2-fluoro-5-(trifluoromethyl)phenol (323 mg, 1.79 mmol) and K _{2 CO 3 (331 mg, 2.39} mmol) of CH ₃ CN (4 mL), followed intermediate 6 and the procedure of step 1 title compound was prepared to give 330 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.86 (d, J = 8.4 Hz, 1H), 8.73 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 5.7 Hz, 1H), 8.05 (d, J = 6.0 Hz, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.81 - 7.68 (m, 2H).

Step 2: Preparation of 1-(2-fluoro-5-(trifluoromethyl)phenoxy)isoquinoline-5-amine

Use 1-(2-fluoro-5-(trifluoromethyl)phenoxy)-5-nitroisoquinoline (320 mg, 0.90 mmol), iron powder (500 mg, 9.09 mmol) and NH ₄ Cl (389 mg, 7.2 mmol) of EtOAc (EtOAc) (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 7.89 (d, J = 5.7 Hz, 1H), 7.75-7.59 (m, 4H), 7.50 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.03 (s, 2H); MS (m/z): 323.28 (M+H) ⁺ .

Intermediate 37

7-Methyl- N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

Step 1: Preparation of 4-methyl-2-nitrobenzamide

To a solution of 4-methyl-2-nitrobenzoic acid (1.0 g, 5.52 mmol) in toluene (5 mL), EtOAc (EtOAc) The reaction mixture was stirred for 2 hours. The reaction mixture was then concentrated and the concentrate was dissolved in THF (5 mL). NH ₄ OH (1.93 g, 55.20 mmol) was then added to the solution and the reaction mixture was stirred at room temperature for 4 hr then quenched with water and EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 1.6 g of desired product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.08 (br s, 1H), 7.79 (s, 1H), 7.62 (br s, 1H), 7.57-7.50 (m, 2H), 2.41 (s, 3H).

Step 2: Preparation of 2-amino-4-methylbenzamide

Using EtOH (8 mL) containing 4-methyl-2-nitrobenzamide (1.60 g, 8.88 mmol), iron powder (2.97 g, 53.33 mmol) and NH ₄ Cl (2.85 g, 53.33 mmol) The title compound was prepared in water (2 mL), m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.62 (br s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 6.93 (br s, 1H), 6.53 (s, 2H), 6.46 (s, 1H), 6.29 (d, J = 7.8 Hz, 1H), 2.15 (s, 3H).

Step 3: Preparation of 7-methylquinazoline-4(3 H )-one

A suspension of 2-amino-4-methylbenzamide (1.2 g, 8.0 mmol) in CH (OEt) ₃ (10 mL) was warmed in EtOAc. Followed by reaction was quenched with aqueous NaHCO ₃ at rt and the resulting precipitate was filtered and dried. The solid material was purified by column chromatography to give 1.1 g of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 12.14 (br s, 1H), 8.05 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.34 ( d, J = 7.8 Hz, 1H), 2.45 (s, 3H).

Step 4: Preparation of 5-bromo-7-methylquinazolin-4( 3H )-one

Add bromine (300 μL) to a solution of 7-methylquinazoline-4( 3H )-one (900 mg, 5.63 mmol) in MeOH (180 mg, 5.63 mmol) and AcOH (5.07 g, 84.45 mmol) , 5.63 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then quenched with aqueous sodium thiosulfate solution. The resulting precipitate was filtered and dried to give 900 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 12.24 (br s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 2.48 (s, 3H).

Step 5: Preparation of 5-bromo-7-methyl-8-nitroquinazolin-4( 3H )-one

7-methyl-quinazolin -4 (3 H) 5-bromo at 0 ℃ - one (700 mg, 2.94 mmol) in concentrated H ₂ SO ₄ (10 mL) was added in the fuming HNO ₃ (185 μL, 2.94 mmol) and then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then quenched with water and filtered and dried to give &lt ^{1 H NMR (300 MHz, DMSO-} d 6): δ 12.80 (br s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 2.41 (s, 3H).

Step 6: Preparation of 5-bromo-7-methyl-8-nitro- N- (3-(trifluoromethyl)phenyl)quinazolin-4-amine

It was heated at reflux for 5-bromo-7-methyl-8-nitro-quinazolin -4 (3 H) - one (200 mg, 0.71 mmol) in POCl ₃ (4 mL) in a solution of 4 hours. The reaction mixture was then concentrated and the residue was crystallised from toluene and dried to give 5-bromo-4-chloro-7-methyl-8-nitroquinazoline, which was dissolved in THF (5 mL). The solution was then treated with 3-(trifluoromethyl)aniline (457 mg, 2.84 mmol) and DIPEA (458 mg, 3.55 mmol) and the reaction mixture was stirred at room temperature for 12 h then quenched with water and Extract with EtOAc. The organic layer was washed with EtOAc EtOAc m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.36 (s, 1H), 9.15 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 8.23 (d, J = 8.4 Hz , 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 2.47 (s, 3H); MS (m/z): 427.17 (M) ⁺ .

Step 7: Preparation of 7-methyl- N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine

To 5-bromo-7-methyl-8-nitro- N- (3-(trifluoromethyl)phenyl)quinazolin-4-amine (400 mg, 0.94 mmol) in EtOH (10 mL) 10% Pd/C (420 mg) was added to the solution and the suspension was stirred at H ₂ (1 atm) for 5 hours. The reaction mixture was then filtered through celite and concentrated. The residue was purified by column chromatography to give 200 mg of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.73 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.65-7.58 (m, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 5.63 (br s, 2H), 2.80 (s, 3H).

Intermediate 38

4-ethoxyquinazoline-8-amine

Step 1: Preparation of 4-ethoxy-8-nitroquinazoline

A solution of 8-nitroquinazolin-4( 3H )-one (Intermediate 7, Step 1, ₃₀₀ mg, 1.57 mmol) in POCl3 (3 mL). The reaction mixture was concentrated and dried to give 4-chloro-8-nitroquinazoline, which was used in the next step without further purification. NaH (263 mg, 11.54 mmol, 95%) was then added to EtOH (2 mL) at 0 ° C and stirred at rt for 15 min then added to 4-chloro-8-nitro A solution of quinazoline in THF (2 mL). The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was then quenched with water and EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 200 mg of title product. MS (m/z): 220.23 (M+H) ⁺ .

Step 2: Preparation of 4-ethoxyquinazolin-8-amine

Containing 4-ethoxy-8-nitro-quinazoline (200 mg, 0.91 mmol), NH 4 Cl (146 mg, 2.74 mmol) and iron powder (153 mg, 2.74 mmol) of EtOH (2 mL) and The title compound was prepared in water (0.5 mL), m. MS (m/z): 190.14 (M+H) ⁺ .

Intermediate 39

N ¹ -(2-fluoro-4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

Step 1: Preparation of N- (2-fluoro-4-(trifluoromethyl)phenyl)-5-nitroisoquinolin-1-amine

Containing 1-chloro-5-nitro-isoquinoline (intermediate 1, step 1,250 mg, 1.19 mmol) and 2-fluoro-4- (trifluoromethyl) aniline (330 mg, 1.84 mmol) of N - Methylpyrrolidone (2 mL), m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.69 (s, 1H), 8.84 (d, J = 7.8 Hz, 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 5.7 Hz, 1H), 7.86-7.57 (m, 5H); MS (m/z): 352.18 (M+H) ⁺ .

Step 2: Preparation of N ¹ -(2-fluoro-4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

Using N- (2-fluoro-4-(trifluoromethyl)phenyl)-5-nitroisoquinolin-1-amine (190 mg, 0.54 mmol), iron powder (303 mg, 5.41 mmol) and _{NH 4 Cl (232 mg, 4.32} mmol) of _{EtOH: H 2 O (3:} 1,4 mL), intermediate 1 followed the procedure of step 2 the title compound was prepared to give 120 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.93 (s, 1H), 7.89 (t, J = 8.4 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.64 (d, J = 10.8 Hz, 1H), 7.51 (t, 8.4 Hz, 2H), 7.40 (d, J = 6.0 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H0, 6.84 (d, J = 7.2 Hz, 1H) ), 5.83 (s, 2H); MS (m/z): 322.33 (M+H) ⁺ .

Intermediate 40

N ¹ -(4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

Step 1: Preparation of 5-nitro- N- (4-(trifluoromethyl)phenyl)isoquinolin-1-amine

N -methylpyrrole containing 1-chloro-5-nitroisoquinoline (Intermediate 1, step 1,500 mg, 2.30 mmol) and 4-(trifluoromethyl)aniline (772 mg, 4.70 mmol) was used. The title compound was prepared according to the procedure described in Step 2 to give 750 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.83 (s, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 7.2 Hz, 1H), 8.26 (d, J) = 6.3 Hz, 1H), 8.06 (d, J = 9.0 Hz, 2H), 8.33 (t, J = 7.8 Hz, 1H), 7.66 (m, 3H); MS (m/z): 334.19 (M+H ) ⁺ .

Step 2: Preparation of N ¹ -(4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

Use 5-nitro- N- (4-(trifluoromethyl)phenyl)isoquinolin-1-amine (750 mg, 2.25 mmol), iron powder (1.26 g, 22.5 mmol) and NH ₄ Cl ( 963 mg, 18.0 mmol) of _{EtOH-H 2 O (5:} 2,7 mL), followed intermediate 1, the procedure described in step 3 to give the title compound was prepared 260 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.27 (s, 1H), 8.09 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 6.0 Hz, 1H), 7.64 (m, 3H) ), 7.44 (d, J = 5.7 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.87 (br s, 2H); MS (m/) z): 304.28 (M+H) ⁺ .

Intermediate 41

1-(4-(trifluoromethyl)phenoxy)isoquinolin-5-amine

Step 1: Preparation of 5-nitro-1-(4-(trifluoromethyl)phenoxy)isoquinoline

Use 1-chloro-5-nitroisoquinoline (step 1, intermediate 1,500 mg, 2.39 mmol), 4-(trifluoromethyl)phenol (776 mg, 4.79 mmol) and K ₂ CO ₃ ( 989 mg, 7.17 mmol) of CH ₃ CN (5 mL), followed intermediate 6, in the procedure of step 1 title compound was prepared to give 800 mg of the title product. MS (m/z): 335.09 (M+H) ⁺ .

Step 2: Preparation of 1-(4-(trifluoromethyl)phenoxy)isoquinolin-5-amine

Using 5-nitro-1-(4-(trifluoromethyl)phenoxy)isoquinoline (800 mg, 2.39 mmol), iron powder (1.34 g, 23.9 mmol) and NH ₄ Cl (1.02 g, The title compound was prepared according to the procedure described in Step 3 of Intermediate 1 to give the title product (140 mg). ¹ H NMR (300 MHz, DMSO d ₆ ): δ 7.81 (m, 3H), 7.72 (d, 1H), 7.46-7.40 (m, 4H), 6.94 (d, J = 6.9 Hz, 1H), 6.03 ( s, 2H); MS (m/z): 305.17 (M+H) ⁺ .

Intermediate 42

1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-amine

Step 1: Preparation of 1-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-nitroisoquinoline

Use 1-chloro-5-nitroisoquinoline (step 1, intermediate 1,500 mg, 2.38 mmol), 4-fluoro-3-(trifluoromethyl)phenol (859 mg, 4.77 mmol) and K _{2 CO 3 (821 mg, 5.95} mmol) of CH ₃ CN (5 mL), followed intermediate 6, in the procedure of step 1 title compound was prepared to give 850 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.84 (d, J = 8.4 Hz, 1H), 8.71 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 6.3 Hz, 1H), 8.01 - 7.92 (m, 2H), 7.87 (m, 1H), 7.76 (m, 1H), 7.66 (t, J = 9.6 Hz, 1H); MS (m/z): 353.20 (M+H) ⁺ .

Step 2: Preparation of 1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-amine

Use 1-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-nitroisoquinoline (830 mg, 2.35 mmol), iron powder (1.31 mg, 23.5 mmol) and NH ₄ Cl (1.09 g, 18.8 mmol) <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; ¹ H NMR (300 MHz, DMSO d ₆ ): δ 7.79 (d, J = 6.0 Hz, 1H), 7.71-7.56 (m, 4H), 7.51 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.01 (s, 2H).

Intermediate 43

6-chloro-2-methoxy-3-(pentamylaminomethyl)benzoic acid

To ethyl 6-chloro-2-fluoro-3-(pentamylamino)benzoate (Intermediate 2; Step 2, 1.00 g, 3.31 mmol) in THF:MeOH:H ₂ O (2:2) KOH (930 mg, 16.57 mmol) was added to the solution in :1; 5 mL). The reaction mass was heated at 100 ° C for 3 hours in a sealed tube. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and washed with water and brine. The organic layer was separated, dried, filtered and concentrated to give &lt ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 13.65 (br s, 1H), 8.08 (t, 1H), 7.29-7.26 (d, J = 8.4 Hz, 1H), 7.22-7.19 (d, J = 8.7 Hz, 1H), 4.25 (d, J = 5.7 Hz, 2H), 3.79 (s, 3H), 1.13 (s, 9H); MS (m/z): 300.05 (M+H) ⁺ .

Intermediate 44

4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinoline-8-amine

Step 1: Preparation of 4-(4-fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinoline

Using 4-chloro-8-nitroquinoline (Intermediate 11, Step 2, 250 mg, 1.20 mmol), 4-fluoro-3-(trifluoromethyl)phenol (430 mg, 2.40 mmol), K _{2 CO 3 (479 mg, 3.60 mmol} ) of CH ₃ CN (5 mL), intermediate 11 following the step in the procedure the title compound was prepared 3 to give 380 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 10.75 (s, 1H), 8.82 (d, J = 5.4 Hz, 1H), 7.92 (m, 1H), 7.86-7.81 (m, 3H), 7.31 ( t, J = 9.6 Hz, 1H), 6.90 (d, J = 5.1 Hz, 1H); MS (m/z): 353.14 (M+H) ⁺ .

Step 2: Preparation of 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinoline-8-amine

Use 4-(4-fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinoline (380 mg, 1.07 mmol), iron powder (604 mg, 10.79 mmol) and NH ₄ Cl ( 461 mg, 8.63 mmol) of EtOAc (3 mL) EtOAc. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.55 (d, J = 4.8 Hz, 1H), 7.75 (d, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.34 (d, J = 4.5 Hz, 2H), 6.92 (t, 1H), 6.68 (d, J = 4.8 Hz, 1H), 5.98 (s, 2H); MS (m/z): 323.28 (M+H) ⁺ .

Intermediate 45

4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazolin-8-amine

Step 1: Preparation of 4-(4-fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinazoline

Using 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 500 mg, 2.38 mmol), 4-fluoro-3-(trifluoromethyl)phenol (859 mg, 4.77 mmol) and NaH (150 mg, 5.95 mmol, 60% in mineral oil) THF (10 mL). ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.89 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 6.9 Hz, 1H), 7.99-7.94 (m, 2H), 7.86-7.84 (m, 1H), 7.71 (t, J = 9.6 Hz, 1H); MS (m/z): 354.13 (M+H) ⁺ .

Step 2: Preparation of 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazolin-8-amine

Use 4-(4-fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinazoline (830 mg, 2.35 mmol), NH ₄ Cl (1.00 g, 18.8 mmol) and iron powder (1.31 g, 23.5 mmol) <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.60 (s, 1H), 7.88 (m, 1H), 7.76 (m, 1H), 7.66 (t, J = 9.6 Hz, 1H), 7.45 (d) , J = 9.3 Hz, 2H), 7.10 (d, J = 5.7 Hz, 1H), 6.08 (s, 2H); MS (m/z): 324.23 (M+H) ⁺ .

Intermediate 46

4-(4-(trifluoromethyl)phenoxy)quinoline-8-amine

Step 1: Preparation of 8-nitro-4-(4-(trifluoromethyl)phenoxy)quinoline

Using 4-chloro-8-nitroquinoline (Intermediate 11, Step ₂ , ₂₀₀ mg, 0.96 mmol), 4-(trifluoromethyl)phenol (233 mg, 1.43 mmol), K ₂ CO ₃ (264 mg, 1.91 mmol) of CH ₃ CN (5 mL), intermediate 11 followed the procedure of the step 3 title compound was prepared to give 200 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.85 (d, J = 4.8 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.82 (t, J = 8.1 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 5.4 Hz, 1H).

Step 2: Preparation of 4-(4-(trifluoromethyl)phenoxy)quinoline-8-amine

Use 8-nitro-4-(4-(trifluoromethyl)phenoxy)quinoline (200 mg, 0.59 mmol), iron powder (335 mg, 5.98 mmol) and NH ₄ Cl (260 mg, 4.70) The title compound was obtained from EtOAc EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.60 (d, J = 4.8 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 5.4 Hz, 1H), 6.01 (s) , 2H).

Intermediate 47

N ⁴ -(4,4-dimethylcyclohexyl)-2-methylquinazoline-4,8-diamine

Step 1: Preparation of N- (4,4-dimethylcyclohexyl)-2-methyl-8-nitroquinazolin-4-amine

Using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate 27, Step 2, 217 mg, 0.97 mmol), 4,4-dimethylcyclohexylamine hydrochloride (477 mg, 2.9 mmol) and _{K 2 CO 3 (402 mg,} 2.9 mmol) of CH ₃ CN (5 mL), intermediate 15 followed, in the procedure of step 1 title compound was prepared to give 265 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.50 (d, J = 8.1 Hz, 1H), 8.20-8.13 (m, 2H), 7.53 (t, J = 8.4 Hz, 1H), 4.15 (m, 1H), 2.42 (s, 3H), 1.73 (m, 2H), 1.67-1.55 (m, 2H), 1.45-1.28 (m, 4H), 0.97 (s, 3H), 0.94 (s, 3H); [M+H] ⁺ : 315.23.

Step 2; Preparation of N ⁴ -(4,4-dimethylcyclohexyl)-2-methylquinazoline-4,8-diamine

Using N- (4,4-dimethylcyclohexyl)-2-methyl-8-nitroquinazolin-4-amine (265 mg, 0.84 mmol), NH ₄ Cl (368 mg, 6.74 mmol) The title compound was prepared according to the procedure described in Step 2 to give 200 mg of the title product, EtOAc (EtOAc, EtOAc, EtOAc, ¹ H NMR (300 MHz, DMSO d ₆ ): δ. 7.42 (d, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 8.1 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.56 (s, 2H), 4.11 (m, 1H), 2.42 (s, 3H), 1.69 (m, 2H), 1.62-1.58 (m, 2H), 1.39-1.23 (m, 4H), 0.97 (s, 3H), 0.94 (s, 3H).

Intermediate 48

Quinoline-8-amine

Add 10% Pd/C (75 mg) to a solution of 4-chloro-8-nitroquinoline (Intermediate 11, Step 2, 150 mg, 0.71 mmol) in EtOAc (3 mL) at 20 psi The suspension was hydrogenated in a Parr apparatus for 4 hours. The reaction mixture was then filtered through celite and concentrated. Containing the ₃ CHCl 10% EtOAc, by residue was purified by column chromatography to give 50 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.71 (d, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.47-7.43 (m, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 5.90 (s, 2H).

Intermediate 49

2-methyl-4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine

Step 1: Preparation of 2-methyl-8-nitro-4-(3-(trifluoromethyl)phenoxy) Quinazoline

Using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate 27, Step 2, 500 mg, 2.24 mmol), 4-fluoro-3-(trifluoromethyl)phenol (545 mg, 3.36 mmol) and NaH (107 mg, 4.48 mmol, 60% in EtOAc) EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.63 - 8.60 (d, J = 8.7 Hz, 1H), 8.53 - 8.51 (d, J = 7.8 Hz, 1H), 7.87 (m, 2H), 7.76 (m, 3H), 2.50 (s, 3H); MS (m/z): 350.19 (M+H) ⁺ .

Step 2: Preparation of 2-methyl-4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine

Using 2-methyl-8-nitro-4-(3-(trifluoromethyl)phenoxy)quinazoline (386 mg, 1.10 mmol), NH ₄ Cl (619 mg, 11.0 mmol) and iron The title compound was prepared according to the procedure described in Step 2 to give 120 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.76-7.69 (m, 2H), 7.40-7.36 (m, 2H), 7.12-7.03 (m, 3H), 5.93 (s, 2H), 2.50 ( s, 3H).

Intermediate 50

N ⁴ -isopropyl-2-methylquinazoline-4,8-diamine

Step 1: Preparation of N -isopropyl-2-methyl-8-nitroquinazolin-4-amine

A solution of 4-chloro-2-methyl-8-nitroquinazoline (Intermediate 27, Step 2, 100 mg, 0.45 mmol) in EtOAc (1 mL). The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 60 mg of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.54-8.51 (d, J = 8.4 Hz, 1H), 8.23-8.21 (d, J = 7.5 Hz, 1H), 8.17-8.14 (d, J = 7.8 Hz, 1H), 7.56-7.51 (t, J = 7.8 Hz, 1H), 4.58-4.51 (m, 1H), 2.44 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H).

Step 2: Preparation of N ⁴ -isopropyl-2-methylquinazoline-4,8-diamine

Use N -isopropyl-2-methyl-8-nitroquinazolin-4-amine (60 mg, 0.24 mmol), NH ₄ Cl (103 mg, 1.95 mmol) and iron powder (136 mg, 2.43) The title compound was prepared according to the procedure described in EtOAc (m.) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.17-7.14 (t, J = 7.8 Hz, 1H), 6.91-6.88 (d, J = 7.2 Hz, 2H), 4.82 (br s, 2H), 4.62 4.53 (m, 1H), 2.61 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H).

Intermediate 51

2-methyl-4-(N-morpholinyl)quinazolin-8-amine

Step 1: Preparation of 4-(2-methyl-8-nitroquinazolin-4-yl)morpholine

Use 4-chloro-2-methyl-8-nitroquinazoline (Intermediate 27, Step 2, 280 mg, 1.26 mmol), morpholine (219 mg, 2.52 mmol) and K ₂ CO ₃ (521 mg , 3.78 mmol) of CH ₃ CN (5 mL), intermediate 15 followed, in the procedure of step 1 title compound was prepared to give 270 mg of the title product. MS [M+H] ⁺ : 275.22.

Step 2: Preparation of 2-methyl-4-(N-morpholinyl)quinazolin-8-amine

Use 4-(2-methyl-8-nitroquinazolin-4-yl)morpholine (250 mg, 0.91 mmol), NH ₄ Cl (386 mg, 7.29 mmol) and iron powder (510 mg, 9.12) The title compound was prepared according to the procedure described in EtOAc (m. MS [M+H] ⁺ : 245.30.

Intermediate 52

4-isopropoxy quinazoline-8-amine

Step 1: Preparation of 4-isopropoxy-8-nitroquinazoline

Using 8-nitroquinazolin-4( 3H )-one (Intermediate 7, Step 1, ₃₀₀ mg, 1.57 mmol), POCl3 (3 mL), NaH (277 mg, 10.99 mmol, 95%), ^The title compound was prepared according to the procedure described in Step 1 to give the title compound. MS [M+H] ⁺ : 234.02.

Step 2: Preparation of 4-isopropoxy quinazoline-8-amine

Containing 4-isopropoxy-8-nitro-quinazoline (150 mg, 0.641 mmol), NH 4 Cl (216 mg, 3.85 mmol) and iron powder (205 mg, 3.85 mmol) of EtOH (5 mL) The title compound was prepared in water (1 mL), m. MS [M+H] ⁺ : 204.06.

Intermediate 53

N ⁴ -(4,4-difluorocyclohexyl)-2-methylquinazoline-4,8-diamine

Step 1: Preparation of N- (4,4-difluorocyclohexyl)-2-methyl-8-nitroquinazolin-4-amine

Use 4-chloro-2-methyl-8-nitroquinazoline (Intermediate 27, Step 2, 200 mg, 0.896 mmol), 4,4-difluorocyclohexylamine hydrochloride (228 mg, 1.345 mmol) and _{K 2 CO 3 (370 mg,} 2.68 mmol) of CH ₃ CN (4 mL), followed intermediate 15, step 1 in the procedure of the title compound was prepared to give 200 mg of the title product. MS [M+H] ⁺ : 323.23.

Step 2: Preparation of N ⁴ -(4,4-difluorocyclohexyl)-2-methylquinazoline-4,8-diamine

Using N- (4,4-difluorocyclohexyl)-2-methyl-8-nitroquinazolin-4-amine (200 mg, 0.621 mmol), NH ₄ Cl (263 mg, 4.96 mmol) and Iron powder (347 mg, 6.21 mmol) in EtOAc (4 mL) EtOAc (EtOAc) MS [M+H] ⁺ : 293.27.

Intermediate 54

N ⁴ , N ⁴ -dimethylquinazoline-4,8-diamine

Step 1: Preparation of N , N -dimethyl-8-nitroquinazolin-4-amine

Was heated at reflux for 8-nitro-quinazolin -4 (3 H) - one (Intermediate 7, Step 1,280 mg, 1.46 mmol) in POCl _{3 (3} mL) in the solution for 3 hours. The reaction mixture was concentrated and the residue was crystalljjjjjjjj The solution was then treated with 10% dimethylamine in THF (6 mL) and the mixture was stirred at <RTI ID=0.0></RTI></RTI><RTIgt; The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give &lt ¹ H NMR (400 MHz, DMSO d ₆ ): δ 8.51 (s, 1H), 8.42 - 8.39 (d, J = 8.8 Hz, 1H), 8.23 - 8.21 (d, J = 7.6 Hz, 1H), 7.57- 7.53 (t, J = 8.0 Hz, 1H), 3.31 (s, 6H); MS[M+H] ⁺ : 219.12.

Step 2: Preparation of N ⁴ , N ⁴ -dimethylquinazoline-4,8-diamine

Use N , N -dimethyl-8-nitroquinazolin-4-amine (170 mg, 0.78 mmol), NH ₄ Cl (333 mg, 6.24 mmol) and iron powder (436 mg, 7.80 mmol) The title compound was prepared from EtOAc (EtOAc) (EtOAc) ¹ H NMR (400 MHz, DMSO d ₆ ): δ 8.42 (s, 1H), 7.23 - 7.14 (m, 2H), 6.90-6.88 (dd, J = 1.2, 7.2 Hz, 1H), 5.74 (br s, 2H), 3.29 (s, 6H); MS [M+H] ⁺ : 189.27.

Intermediate 55

N ⁴ -(t-butyl)quinazoline-4,8-diamine

Step 1: Preparation of N- (t-butyl)-8-nitroquinazolin-4-amine

Stir 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 500 mg, 2.39 mmol) and tert-butylamine (350 mg, 4.78 mmol) in pyridine (5 mL). The solution was 3 hours. The reaction mixture was then concentrated and the residue was crystallised from EtOAc. The solution was washed with water and brine, dried, dried, filtered, evaporated. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.67 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H) , 7.63 - 7.58 (t, J = 8.0 Hz, 1H), 1.54 (s, 9H); MS [M+H] ⁺ : 247.18.

Step 2: Preparation of N ⁴ -(t-butyl)quinazoline-4,8-diamine

Use N- (tert-butyl)-8-nitroquinazolin-4-amine (300 mg, 1.22 mmol), NH ₄ Cl (653 mg, 12.2 mmol) and iron powder (194 mg, 3.66 mmol) The title compound was prepared following EtOAc (EtOAc) (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.38 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.17-7.11 (t, J = 7.8 Hz, 1H), 6..93 (s, 1H), 6.85 (d, J = 7.8 Hz, 1H), 5.69 (s, 2H), 1.53 (s, 9H); MS[M+H] ⁺ : 217.11.

Intermediate 56

4-ethoxyquinoline-8-amine

Step 1: Preparation of 4-chloroquinoline-8-amine

Use EtOH (containing 4-chloro-8-nitroquinoline (Intermediate 11, Step 2, 250 mg, 1.20 mmol), NH ₄ Cl (513 mg, 9.60 mmol), and iron powder (671 mg, 12.0 mmol). 6 mL) and water (3 mL), m. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.69 ((d, J = 4.6 Hz, 1H), 7.55-7.53 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 4.6 Hz, 1H) , 7.46-7.42 (t, J = 7.6 Hz, 1H), 7.00-6.98 (d, J = 7.6 Hz, 1H), 5.06 (br s, 2H); MS[M+H] ⁺ : 179.25.

Step 2: Preparation of 4-ethoxyquinolin-8-amine

NaH (141 mg, 5.6 mmol, 95%) was added to a solution of ethanol (5 mL) at 0 ° C and the reaction mixture was stirred at room temperature for 30 min, then 4-chloroquinoline-8-amine (200 mg, 1.12 mmol) to the reaction mixture. The reaction mixture was then heated at 110 ° C for 12 hours in a sealed tube, which was then quenched with 1 N HCl. The reaction mixture was extracted with chloroform and the organic layer was washed with brine. The residue was purified by column chromatography to give &lt MS [M+H] ⁺ : 189.15.

Intermediate 57

N ⁴ -isopropyl quinazoline-4,8-diamine

Step 1: Preparation of N -isopropyl-8-nitroquinazolin-4-amine

Using 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 300 mg, 1.43 mmol) and isopropylamine (169 mg, 2.86 mmol) in pyridine (5 mL) The title compound was prepared by the procedure described in 1 to give 250 mg of the title product. ¹ H NMR (400 MHz, DMSO d ₆ ): δ 8.58-8.56 (d, J = 8.4 Hz, 1H), 8.51 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.23-8.20 ( d, J = 7.6 Hz, 1H), 7.63 - 7.59 (t, J = 8.0 Hz, 1H), 4.55-4.50 (m, 1H), 1.27 (s, 3H), 1.26 (s, 3H); MS [M +H] ⁺ : 233.14.

Step 2: Preparation of N ⁴ -isopropylquinazoline-4,8-diamine

Containing _{N - NH 4 Cl (576 mg} , 10.76 mmol) and iron powder (172 mg, 3.24 mmol) of EtOH-isopropyl-8-nitro-quinazolin-4-amine (250 mg, 1.08 mmol), ( 4 mL) and water (1 mL), m. ¹ H NMR (400 MHz, DMSO d ₆ ): δ 8.35 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.35-7.33 (d, J = 8.0 Hz, 1H), 7.16-7.12 ( t, J = 8.0 Hz, 1H), 6.86-6.84 (d, J = 8.0 Hz, 1H), 5.66 (br s, 2H), 4.51-4.45 (m, 1H), 1.24 (s, 3H), 1.22 ( s, 3H); MS [M+H] ⁺ : 203.17.

Intermediate 58

N ⁴ -(t-butyl)-2-methylquinazoline-4,8-diamine

Step 1: Preparation of N- (t-butyl)-2-methyl-8-nitroquinazolin-4-amine

Use 4-chloro-2-methyl-8-nitroquinazoline (Intermediate 27, Step 2, 300 mg, 1.34 mmol) and butylamine (196 mg, 2.68 mmol) in pyridine (5 mL) The title compound was prepared following the procedure described in Step 1 to afford 200 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.62-8.59 (d, J = 8.1 Hz, 1H), 8.16-8.13 (d, J = 7.5 Hz, 1H), 7.61 (s, 1H), 7.51 ( t, J = 7.8 Hz, 1H), 2.45 (s, 3H), 1.55 (s, 9H); MS (m/z): 261.20 (M+H) ⁺ .

Step 2: Preparation of N ⁴ -(t-butyl)-2-methylquinazoline-4,8-diamine

Using N- (t-butyl)-2-methyl-8-nitroquinazolin-4-amine (200 mg, 0.77 mmol), NH ₄ Cl (411 mg, 7.68 mmol) and iron powder (83 The title compound was obtained after the title compound was obtained from mjjjjjjjjjj ¹ H NMR (300 MHz, DMSO d ₆ ): δ 7.35-7.33 (d, J = 7.8 Hz, 1H), 7.09-7.03 (t, J = 7.8 Hz, 1H), 6.82-6.79 (m, 2H), 5.57 (s, 2H), 2.46 (s, 3H), 1.53 (s, 9H); MS (m/z): 231.26 (M+H) ⁺ .

Intermediate 59

6-Chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropionamido)methyl)benzoic acid

Step 1: Preparation of ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropionamido)methyl)benzoate

To 3-(aminomethyl)-6-chloro-2-fluorobenzoic acid ethyl ester (Intermediate 2, Step 1, 800 mg, 3.45 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (591 Mg, 5.00 mmol) hexafluorophosphate (benzotriazol-1-yloxy) ginseng (dimethylamino) hydrazine (2.29 g, 5.18 mmol) and DIPEA (1.29) in DMF (5 mL) g, 10.0 mmol). Followed by stirring at room temperature for 12 hours and the reaction mixture was diluted with EtOAc, washed with H ₂ O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to give &lt ¹ H NMR (400 MHz, DMSO d ₆ ): δ 8.09-8.06 (t, J = 8.0 Hz, 1H), 7.45-7.38 (m, 2H), 4.91-4.88 (t, J = 5.2 Hz, 1H), 4.42-4.37 (q, J = 8.0 Hz, 2H), 4.29-4.28 (d, J = 5.6 Hz, 2H), 3.48 (m, 2H), 1.33-1.29 (t, J = 8.0 Hz, 3H), 1.05 (s, 6H).

Step 2: Preparation of 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropionamido)methyl)benzoic acid

Ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropionamido)methyl)benzoate (712 mg, 2.15 mmol) in THF:MeOH:H ₂ O (2: 1:1; 8 mL) and NaOH (344 mg, 8.60 mmol). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.08-8.05 (t, J = 8.0 Hz, 1H), 7.36-7.33 (m, 2H), 4.90 (t, 1H), 4.29 - 4.28 (d, J = 6.0 Hz, 2H), 3.38 (m, 2H), 1.06 (s, 6H).

Intermediate 60

6-chloro-2-fluoro-3-(isobutylguanidinomethyl)benzoic acid

Step 1: Preparation of ethyl 6-chloro-2-fluoro-3-(isobutylguanidinomethyl)benzoate

Ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate 2, Step 1, 1.00 g, 4.32 mmol), Isobutylphosphonium chloride (690 mg, 6.48 mmol) and DIPEA (yield) 1.67 g, 12.96 mmol) of THF (30 mL).

Step 2: Preparation of 6-chloro-2-fluoro-3-(isobutylguanidinomethyl)benzoic acid

Ethyl 6-chloro-2-fluoro-3-(isobutylguanidinomethyl)benzoate (1.00 g, 3.31 mmol) and NaOH (530 mg, 13.26 mmol) in THF:MeOH:H ₂ O ( 3:2:1; 12 mL), mp. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 14.10 (s, 1H), 8.32 (br, 1H), 7.38-7.29 (m, 2H), 4.25 (d, J = 5.1 Hz, 2H), 2.4.0 (m, 1H), 1.00 (d, J = 6.9 Hz, 6H).

Intermediate 61

Methyl 5-(aminomethyl)-2-chloro-4-fluorobenzoate

Intermediate 62

Methyl 3-(aminomethyl)-2-chloro-4-fluorobenzoate

Step 1: Preparation of 2-chloro-4-fluoro-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid and 2-chloro-4-fluoro-3-((2,2) ,2-trifluoroacetamido)methyl)benzoic acid

A concentrated H ₂ SO containing 2-chloro-4-fluorobenzoic acid (10.0 g, 57.29 mmol) and 2,2,2-trifluoro- N- (hydroxymethyl)acetamide (9.02 g, 63.02 mmol). _The title compound was obtained as a m. m.

Step 2: Preparation of 5-(((t-butoxycarbonyl)amino)methyl)-2-chloro-4-fluorobenzoic acid and 3-(((t-butoxycarbonyl)amino)methyl -2-chloro-4-fluorobenzoic acid

The positional isomer mixture obtained from step 1 (12.0 g, 40.05 mmol), concentrated HCl (30 mL), dioxane (50 mL), dibutyl succinate (10.48 g, 48.06 mmol), NaOH ( 2.4 g, 60.08 mmol), THF (40 mL) and H ₂ O (5 mL), followed intermediate 5, the procedure of step 2 to give the title compound was prepared in the form of 4.5 g of product as a regioisomeric mixture of the title The product was taken to the next step without further purification.

Step 3: Preparation of methyl 5-(((t-butoxycarbonyl)amino)methyl)-2-chloro-4-fluorobenzoate and 3-(((t-butoxycarbonyl)amino) Methyl)-2-chloro-4-fluorobenzoic acid methyl ester

A DMF (25 mL) containing the regioisomeric mixture (4.50 g, 14.82 mmol), methyl iodide (3.11 g, 22.23 mmol) and K ₂ CO ₃ (6.14 g, 44.46 mmol) obtained from step 2 was used. The title compound was prepared by the procedure described in Step 5 to give 3.2 g of the title product as a mixture.

Step 4: Preparation of methyl 5-(aminomethyl)-2-chloro-4-fluorobenzoate and methyl 3-(aminomethyl)-2-chloro-4-fluorobenzoate

A solution of the regioisomeric mixture (3.00 g, 9.44 mmol) from EtOAc (10 mL) With 1 N NaOH solution and the reaction mixture was at 0 ℃ and CHCl 5% MeOH containing extracted ₃ of. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 400 mg of intermediate 61 and 200 mg of intermediate 62. Intermediate 61: ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.03-8.01 (d, J = 8.1 Hz, 1H), 7.53-7.50 (d, J = 9.9 Hz, 1H), 3.85 (s, 3H), 3.74 (s, 2H). Intermediate 62: ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.75-7.69 (dd, J = 6.9, 14.7 Hz, 1H), 7.36-7.29 (t, J = 9.3 Hz, 1H), 3.85- 3.83 (m, 5H).

Intermediate 63

2-chloro-4-fluoro-5-(pentamylaminomethyl)benzoic acid

Step 1: Preparation of methyl 2-chloro-4-fluoro-5-(pentamylaminomethyl)benzoate

Use methyl 5-(aminomethyl)-2-chloro-4-fluorobenzoate (180 mg, 0.83 mmol), DIPEA (321 mg, 2.49 mmol) and trimethylethyl hydrazine chloride (120 mg, 1.0 mmol) ) of _{CH 2 Cl 2 (5 mL)} , in the step 2 of intermediate 2 following the procedure of the title compound was prepared to give 250 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.16 (t, 1H), 7.73 (d, J = 6.9 Hz, 1H), 7.58-7.54 (d, J = 10.2 Hz, 1H), 4.26-4.24 (d, J = 5.7 Hz, 2H), 3.83 (s, 3H), 1.11 (s, 9H).

Step 2: Preparation of 2-chloro-4-fluoro-5-(pentamylaminomethyl)benzoic acid

Use of 2-chloro-4-fluoro-5- (pivaloyl acyl amino methyl) benzoate (250 mg, 0.83 mmol) of _{THF: MeOH: H 2 O (} 3: 2: 1; 6 mL) The title compound was prepared following EtOAc (EtOAc, m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.17-8.14 (t, J = 6.0 Hz, 1H), 7.76-7.73 (d, J = 8.4 Hz, 1H), 7.53-7.50 (d, J = 9.9 Hz, 1H), 4.26 (d, J = 5.7 Hz, 2H), 1.12 (s, 9H).

Intermediate 64

2-chloro-4-fluoro-3-(pentamylaminomethyl)benzoic acid

Step 1: Preparation of 2-chloro-4-fluoro-3-(pentamylaminomethyl)benzoic acid ester

Methyl 3-(Aminomethyl)-2-chloro-4-fluorobenzoate (340 mg, 1.42 mmol), DIPEA (550 mg, 4.27 mmol) and trimethylethyl chlorobenzene (204 mg, 1.7 mmol) ) of _{CH 2 Cl 2 (5 mL)} , in the step 2 of intermediate 2 following the procedure of the title compound was prepared to give 350 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.81-7.74 (m, 2H), 7.36-7.30 (t, J = 9.0 Hz, 1H), 4.39 - 4.37 (d, J = 4.5 Hz, 2H) , 3.85 (s, 3H), 1.06 (s, 9H).

Step 2: Preparation of 2-chloro-4-fluoro-3-(pentamylaminomethyl)benzoic acid

Use of 2-chloro-4-fluoro-3- (pivaloyl acyl aminomethyl) benzoate (350 mg, 1.16 mmol) of _{THF: MeOH: H 2 O (} 3: 2: 1; 6 mL) The title compound was prepared following EtOAc (EtOAc, m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 12.55 (br s, 1H), 7.78 (m, 2H), 7.32 - 7.26 (t, J = 8.7 Hz, 1H), 4.38 (d, J = 4.5) Hz, 2H), 1.07 (s, 9H).

Intermediate 65

N ⁴ -(2,2,2-trifluoroethyl)quinazoline-4,8-diamine

Step 1: Preparation of 8-nitro- N- (2,2,2-trifluoroethyl)quinazolin-4-amine

Use pyridine (2 mL) containing 4-chloro-8-nitroquinazoline (Intermediate 7, Step 2, 400 mg, 1.91 mmol) and 2,2,2-trifluoroethylamine (189 mg, 1.91 mmol) The title compound was prepared following the procedure described in Step 1 to afford 85 mg of the title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 9.22 (t, 1H), 8.66 (s, 1H), 8.61 - 8.59 (d, J = 8.4 Hz, 1H), 8.36 - 8.34 (d, J = 7.8 Hz, 1H), 7.77-7.72 (t, J = 8.1 Hz, 1H), 4.52-4.44 (m, 2H); MS[M+H] ⁺ : 273.41.

Step 2: Preparation of N ⁴ -(2,2,2-trifluoroethyl)quinazoline-4,8-diamine

Use 8-nitro- N- (2,2,2-trifluoroethyl)quinazolin-4-amine (80 mg, 0.29 mmol), NH ₄ Cl (63 mg, 1.17 mmol) and iron powder ( 65 mg, 1.17 mmol) of EtOAc (2 mL) EtOAc (EtOAc) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.47 (m, 2H), 7.36-7.33 (d, J = 8.4 Hz, 1H), 7.27-7.22 (t, J = 7.8 Hz, 1H), 6.94 6.91 (d, J = 7.8 Hz, 1H), 5.84 (br s, 2H), 4.44 - 4.39 (m, 2H); MS[M+H] ⁺ : 243.45.

Intermediate 66

2-(Difluoromethyl)-5-(isobutylguanidinomethyl)nicotinic acid

Step 1: Preparation of (Z)-2-(ethoxymethylene)-4,4-difluoro-3-indolyl Ethyl butyrate

To a freshly prepared solution of sodium ethoxide in EtOH (prepared by the addition of 1.11 g, 48.35 mmol of Na metal in 8 mL of EtOH), ethyl difluoroacetate (5.0 g, 40.29 mmol). The solution in mL) and the reaction mixture was heated at 65 °C for 2 hours. The reaction mixture was then quenched with 1 N HCl at rt and pH was adjusted to 6-7. The reaction mixture was extracted with EtOAcq~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ One step. Add acetic anhydride (27.0 g, 265.0 mmol) to a mixture of 4,4-difluoro-3-oxobutyric acid ethyl ester (5.5 g, 33.11 mmol) and triethyl orthoformate (12 mL, 66.26 mmol) The reaction mixture was heated at 100 ° C for 12 hours. The reaction mixture was then concentrated to give EtOAc (EtOAc)

Step 2: Preparation of ethyl 5-cyano-2-(difluoromethyl)nicotinate

Add N , N -dimethylformamide dimethylacetal (3.35 g, 28.23 mmol) to a solution of cyanoacetic acid (2.0 g, 23.53 mmol) in 1,4-dioxane (10 mL) The reaction mixture was heated at 80 ° C for 4 hours. The reaction mixture was then concentrated, diluted with Et ₂ O and filtered through a pad of silicon dioxide. The filtrate was concentrated to give 2.37 g of (E)-3-(dimethylamino) acrylonitrile which was taken to the next step without further purification. To (Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxobutyric acid ethyl ester (5.5 g, 24.77 mmol) in DMF (15 mL) (E)-3-(Dimethylamino)acrylonitrile (2.37 g, 24.77 mmol) was added dropwise to the solution, and the mixture was stirred at the same temperature for 5 hr. Then added _{NH 4 OAc (2.86 g, 37.15} mmol) to the reaction mixture and the heating was continued for 12 h. The reaction mixture was then quenched with water at rt and extracted with Et ₂ O. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to give &lt ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.09 (s, 1H), 8.60 (s, 1H), 7.62 - 7.26 (t, J = 54 Hz, 1H), 4.51-4.44 (q, J = 7.2 Hz, 2H), 1.46-1.42 (t, J = 7.2 Hz, 3H); MS [M+H] ⁺ : 227.38.

Step 3: Preparation of 5-(((t-butoxycarbonyl)amino)methyl)-2-(difluoromethyl)nicotinate

To 5-cyano-2-(difluoromethyl)nicotinic acid ethyl ester (500 mg, 2.21 mmol), Et ₃ N (0.4 mL, 2.87 mmol) and (Boc) ₂ O (963 mg, 4.42 mmol) 10% Pd/C (300 mg) was added to a solution in EtOH (2 mL) and the mixture was hydrogenated at 40 psi for 2 h. The reaction mixture was then filtered through celite and concentrated. The residue was purified by column chromatography to give 500 mg of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.77 (s, 1H), 8.24 (s, 1H), 7.60-7.27 (t, J = 54 Hz, 1H), 4.48-4.41 (m, 4H) , 1.47-1.40 (m, 12H); MS [M+H] ⁺ : 331.31.

Step 4: Preparation of ethyl 2-(difluoromethyl)-5-(isobutylguanidinomethyl)nicotinate

Ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-(difluoromethyl)nicotinic acid ethyl ester (500 mg, 1.51 mmol) was stirred at room temperature in EtOH containing HCl ( The solution in 2 mL) was 2 hours. The reaction mixture was concentrated and the concentrate was dissolved in DMF (2 mL). The solution was treated with DIPEA (464 mg, 3.60 mmol) and isobutylphosphonium chloride (115 mg, 1.08 mmol) at room temperature. The reaction mixture was stirred for 2 hours, then it was diluted with EtOAc and washed with H ₂ O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 200 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.75 (s, 1H), 8.48 (t, 1H), 8.14 (s, 1H), 7.59-7.24 (t, J = 54 Hz, 1H), 4.39- 4.32 (m, 4H), 2.44 (m, 1H), 1.35-1.29 (t, J = 6.9 Hz, 3H), 1.04-1.02 (d, J = 6.9 Hz, 6H); MS [M+H] ⁺ : 301.36.

Step 5: Preparation of 2-(difluoromethyl)-5-(isobutylguanidinomethyl)nicotinic acid

Add LiOH (70 mg to a solution of 2-(difluoromethyl)-5-(isobutylguanidinomethyl)nicotinic acid ethyl ester (200 mg, 0.66 mmol) in 1,4-dioxane. the reaction, 1.66 mmol) in H ₂ O (1 mL) and stirred in the solution at room temperature for 1 hour. The reaction mixture was then quenched with 1N EtOAc and filtered and dried and evaporated ¹ H NMR (300 MHz, DMSO d ₆ ): δ 13.98 (br s, 1H), 8.72 (s, 1H), 8.45 (t, 1H), 8.17 (s, 1H), 7.67-7.32 (t, J = 54 Hz, 1H), 4.39-4.37 (d, J = 5.7 Hz, 2H), 2.43 (m, 1H), 1.04-1.02 (d, J = 6.6 Hz, 6H).

Intermediate 67

6-Chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropionamido)methyl)benzoic acid

Step 1: Preparation of ethyl 6-chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropionamido)methyl)benzoate

To ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropionamido)methyl)benzoate (Intermediate 59, Step 1, 200 mg, 0.60 mmol) To the solution in THF (2 mL), EtOAc (EtOAc, m. The reaction mixture was then quenched with water and extracted with CHCl _3. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to yieldd <RTIgt; ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.32 (t, 1H), 7.44 - 7.36 (m, 2H), 4.47 - 4.29 (m, 6H), 1.33-1.29 (t, J = 6.9 Hz, 3H ), 1.14 (s, 6H).

Step 2: Preparation of 6-chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropionamido)methyl)benzoic acid

Ethyl 6-chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropionamido)methyl)benzoate (100 mg, 0.30 mmol) in THF:MeOH:H ₂ O (3:2:1; 6 mL) and EtOAc (24 mg, 0.60 mmol) ¹ H NMR (300 MHz, DMSO d ₆ ): δ 8.30 (t, 1H), 7.39-7.29 (m, 2H), 4.47 - 4.28 (m, 4H), 1.14 (s, 6H).

Instance Example 1

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amino) isoquinolin-5-yl) benzene Formamide

To a solution of 6-chloro-2-fluoro-3-(p-amylaminomethyl)benzoic acid (intermediate 2,190 mg, 0.66 mmol) in CH ₂ Cl ₂ (4.0 mL) Chlorine (153 mg, 1.22 mmol) and DMF (1 drop). The reaction mass was stirred at room temperature for 2 hours and then concentrated. The concentrate was dissolved in CH ₂ Cl ₂ (1 mL) and added to N ¹ -(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (intermediate 1) at 0 °C , 100 mg, 0.33 mmol) in CH ₂ Cl ₂ (2 mL) and DIPEA (1.0 mL). The reaction mass was stirred at room temperature for 2 hr then was quenched with water and EtOAc. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 25 mg of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.90 (s, 1H), 9.56 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.23-8.21 (m, 2H), 8.12 (d, J = 6.3 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz) , 1H), 7.47-7.31 (m, 4H), 4.35 (d, J = 5.4 Hz, 2H), 1.15 (s, 9H); MS (m/z): 573.13 (M+H) ⁺ .

Example 2

3-chloro-6- (aminomethyl pivaloyl XI) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amino) isoquinolin-5-yl) pyridine A Amides

Using N ¹ -(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (intermediate 1,70 mg, 0.23 mmol), 3-chloro-6-(p-amylamine Methyl)picolinic acid (intermediate 3,121 mg, 0.45 mmol), ethylene dichloride (85 mg, 0.68 mmol), DMF (1 drop) and DIPEA (89 mg, 0.69 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 15 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.78 (s, 1H), 9.56 (s, 1H), 8.48 (d, J = 8.1 Hz, 1H), 8.36-8.22 (m, 3H), 8.12 -8.03 (m, 3H), 7.71 (t, J = 8.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.31 (d, J = 7.8 Hz, 1H), 4.44 (d, J = 5.7 Hz, 2H), 1.17 (s, 9H); MS (m/z): 556.12 (M+H) ⁺ .

Example 3

2,6-dimethyl-3- (pivaloyl acyl aminomethyl) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amino) isoquinolin-5-yl) benzene Formamide

Using N ¹ -(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (intermediate 1,70 mg, 0.23 mmol), 2,6-dimethyl-3-( CH of p-amylaminomethyl)benzoic acid (intermediate 4,120 mg, 0.45 mmol), ethylene dichloride (85 mg, 0.68 mmol), DMF (1 drop) and DIPEA (89 mg, 0.69 mmol) ₂ Cl ₂ (3 mL), the title compound was prepared by following the procedures described in example 1 to give 10 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.51 (s, 1H), 9.51 (s, 1H), 8.44 (d, 1H), 8.31 (s, 1H), 8.22 (d, 1H), 8.08 (d, 1H), 7.97 (m, 1H), 7.69 (m, 1H), 7.53 (m, 2H), 7.37 (d, 1H), 7.30 (d, 1H), 7.11 (s, 2H), 4.24 ( d, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 1.14 (s, 9H); MS[M+H] ⁺ : 549.15.

Example 4

2-chloro-5- (aminomethyl pivaloyl XI) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amino) isoquinolin-5-yl) benzoyl amine

Using N ¹ -(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (intermediate 1,70 mg, 0.23 mmol), 2-chloro-5-(pivalamylamine) Methyl)benzoic acid (intermediate 5,128 mg, 0.45 mmol), ethylene dichloride (85 mg, 0.68 mmol), DMF (1 drop) and DIPEA (89 mg, 0.69 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 15 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.62 (s, 1H), 9.54 (s, 1H), 8.45 (m, 1H), 8.35 (s, 1H), 8.22 (m, 2H), 8.07 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.53 (m, 3H), 7.44 (s, 1H), 7.33 (m, 2H), 4.32 (m, 2H), 1.15 ( s, 9H); MS [M+H] ⁺ : 555.19.

Example 5

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (1- (3- ( trifluoromethyl) phenoxy) isoquinolin-5-yl) benzoyl amine

Use 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (intermediate 6,70 mg, 0.23 mmol), 6-chloro-2-fluoro-3-(pententylene) Aminomethyl)benzoic acid (intermediate 2,129 mg, 0.45 mmol), ethylene dichloride (85 mg, 0.68 mmol), DMF (1 drop) and DIPEA (89 mg, 0.69 mmol) of CH ₂ Cl ₂ The title compound was prepared (3 mL ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 11.02 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.21 (brt, 1H), 8.10-8.01 (m, 2H), 7.81-7.67 (m, 6H), 7.47-7.36 (m, 2H), 4.34 (m, 2H), 1.15 (s, 9H); MS[M+H] ⁺ : 574.09.

Example 6

3-chloro-6- (aminomethyl pivaloyl XI) - N - (1- (3- ( trifluoromethyl) phenoxy) isoquinolin-5-yl) pyridine A Amides

Use 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (intermediate 6,100 mg, 0.329 mmol), 3-chloro-6-(p-amylaminomethyl) Pyridinecarboxylic acid (intermediate 3,126 mg, 0.46 mmol), ethylene dichloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (129 mg, 1.00 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared following the procedure described in Example 1 to give 20 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.89 (s, 1H), 8.34-8.30 (m, 2H), 8.17 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 8.4 Hz , 1H), 8.00 (d, J = 6.3 Hz, 1H), 7.83 - 7.78 (t, J = 7.8 Hz, 1H), 7.73 - 7.67 (m, 5H), 7.40 (d, J = 8.7 Hz, 1H) , 4.45 (d, J = 6.0 Hz, 2H), 1.17 (s, 9H); MS [M+H] ⁺ : 557.18.

Example 7

2-chloro-5- (aminomethyl pivaloyl XI) - N - (1- (3- ( trifluoromethyl) phenoxy) isoquinolin-5-yl) benzoyl amine

Use 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (intermediate 6,100 mg, 0.329 mmol), 2-chloro-5-(p-amylaminomethyl) Benzoic acid (intermediate 5, 133 mg, 0.493 mmol), ethylene dichloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (129 mg, 1.00 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared following the procedure described in Example 1 to give 31 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.76 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.22 (brt, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.82-7.67 (m, 6H), 7.55 (m, 2H), 7.39 (d, 1H), 4.34 - 4.32 (d, J = 5.7 Hz, 2H ), 1.14 (s, 9H); MS [M+H] ⁺ : 556.16.

Example 8

3-chloro-6- (aminomethyl pivaloyl XI) - N - (4 - ( (3- ( trifluoromethyl) phenyl) amino) quinazolin-8-yl) picolinate Amides

Use N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 7,50 mg, 0.164 mmol), 3-chloro-6-(p-amylamine Methyl)picolinic acid (intermediate 3,85 mg, 0.314 mmol), ethylene dichloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 40 mg of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 11.62 (s, 1H), 10.14 (s, 1H), 8.94 (d, J = 7.8 Hz, 1H), 8.77 (s, 1H), 8.32-8.27 (m, 4H), 8.11 (d, J = 8.7 Hz, 1H), 7.75-7.64 (m, 2H), 7.51-7.46 (m, 2H), 4.49 (d, J = 5.7 Hz, 2H), 1.17 ( s, 9H); MS [M+H] ⁺ : 557.16.

Example 9

3-chloro-6- (aminomethyl pivaloyl XI) - N - (. 4- ( 3- ( trifluoromethyl) phenoxy) quinolin-8-yl) picolinate Amides

Use 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (intermediate 8,50 mg, 0.164 mmol), 3-chloro-6-(p-amylaminomethyl) Pyridinecarboxylic acid (intermediate 3, 88 mg, 0.326 mmol), ethylene dichloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH ₂ Cl ₂ (2 mL) The title compound was prepared following the procedure described in Example 1 to give the title compound. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 11.63 (s, 1H), 9.06 (d, J = 7.8 Hz, 1H), 8.86 (s, 1H), 8.33 (brt, 1H), 8.12 ( d, J = 8.1 Hz, 2H), 7.88-7.82 (m, 2H), 7.76 (m, 3H), 7.48 (d, J = 8.4 Hz, 1H), 4.48 (d, J = 5.4 Hz, 2H), 1.16 (s, 9H); MS [M+H] ⁺ : 558.11.

Example 10

2-chloro-5- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine

Use 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (intermediate 8,50 mg, 0.164 mmol), 2-chloro-5-(p-amylaminomethyl) Benzoic acid (intermediate 5,88 mg, 0.326 mmol), ethylene dichloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH ₂ Cl ₂ (2 mL) The title compound was prepared following the procedure described in Example 1 to give 30 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.35 (s, 1H), 8.92 (d, 1H), 8.77 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.85 (m) , 2H), 7.73 (s, 3H), 7.59-7.53 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 4.29 (d, J = 5.4 Hz, 2H), 1.11 (s, 9H) ;MS[M+H] ⁺ : 557.14.

Example 11

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine

Use 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (intermediate 8, 80 mg, 0.262 mmol), 6-chloro-2-fluoro-3-(pententylene) Aminomethyl)benzoic acid (intermediate 2, 150 mg, 0.521 mmol), ethylene dichloride (98 mg, 0.78 mmol), DMF (1 drop) and DIPEA (101 mg, 0.79 mmol) of CH ₂ Cl ₂ The title compound was prepared (3 mL ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.95 (s, 1H), 8.90 (d, J = 8.1 Hz, 1H), 8.79 (s, 1H), 8.18 (d, J = 6.9 Hz, 2H ), 7.85 (m, 2H), 7.75 (s, 3H), 7.41-7.33 (m, 2H), 4.31 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H); MS [M+H] ⁺ : 575.16.

Example 12

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( (3- ( trifluoromethyl) phenyl) amino) quinazolin-8-yl) benzene Formamide

Using N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 7, 80 mg, 0.263 mmol), 6-chloro-2-fluoro-3-( CH of p-amylaminomethyl)benzoic acid (intermediate 2,150 mg, 0.521 mmol), ethylene dichloride (98 mg, 0.78 mmol), DMF (1 drop) and DIPEA (101 mg, 0.79 mmol) ₂ Cl ₂ (3 mL), the title compound was prepared by following the procedures described in example 1 to give 30 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.64 (s, 1H), 10.14 (s, 1H), 8.80 (d, J = 7.5 Hz, 1H), 8.71 (s, 1H), 8.37 (s) , 2H), 8.23-8.17 (m, 2H), 7.72-7.65 (m, 2H), 7.50-7.39 (3H), 4.30 (d, 2H), 1.14 (s, 9H); MS [M+H] ⁺ :574.14.

Example 13

2-chloro-5- (aminomethyl pivaloyl XI) - N - (4 - ( (3- ( trifluoromethyl) phenyl) amino) quinazolin-8-yl) benzoyl amine

Using N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 7,50 mg, 0.164 mmol), 2-chloro-5-(p-amylamine Methyl)benzoic acid (intermediate 5,88 mg, 0.326 mmol), ethylene dichloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 25 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 10.16 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 8.69 (s, 1H), 8.33 (m) , 2H), 8.23 (m, 2H), 7.75-7.55 (m, 4H), 7.50 (d, J = 6.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 5.4 Hz, 2H), 1.13 (s, 9H); MS [M+H] ⁺ : 556.23.

Example 14

2-Chloro- N- (4-((4,4-difluorocyclohexyl)amino)quinazolin-8-yl)-5-(pentylaminomethyl)benzamide

Use N ⁴ -(4,4-difluorocyclohexyl)quinazoline-4,8-diamine (intermediate 9,60 mg, 0.215 mmol), 2-chloro-5-(pentamylamine) Benzoic acid (intermediate 5,116 mg, 0.431 mmol), ethylene dichloride (81 mg, 0.65 mmol), DMF (1 drop) and DIPEA (84 mg, 0.65 mmol) in CH ₂ Cl ₂ (3 mL) The title compound was prepared following the procedure described in Example 1 to give 25 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.13 (s, 1H), 8.71 (d, 1H), 8.49 (s, 1H), 8.19 (m, 2H), 8.05 (d, 1H), 7.57 -7.54 (m, 3H), 7.41 (d, 1H), 4.41 (m, 1H), 4.31 (d, 2H), 2.00 (m, 6H), 1.75 (m, 2H), 1.12 (s, 9H); MS (m/z): 530.20 (M+H) ⁺ .

Example 15

2-Chloro- N- (4-((4,4-dimethylcyclohexyl)oxy)quinazolin-8-yl)-5-(pentamylaminomethyl)benzamide

Use 4-((4,4-dimethylcyclohexyl)oxy)quinazoline-8-amine (intermediate 10, 50 mg, 0.185 mmol), 2-chloro-5-(p-amylamine Methyl)benzoic acid (intermediate 5,99 mg, 0.369 mmol), ethylene dichloride (70 mg, 0.55 mmol), DMF (1 drop) and DIPEA (72 mg, 0.56 mmol) of CH ₂ Cl ₂ (3 The title compound was prepared following the procedure described in Example 1 to afford 50 mg title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 8.80 (s, 2H), 8.18 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.73-7.71 (m, 1H), 7.59-7.54 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 5.38 (m, 1H), 4.30 (d, J = 6.0 Hz, 2H), 1.95 (m, 2H), 1.81 (m, 2H), 1.51 (m, 2H), 1.34 (m, 2H), 1.12 (s, 9H), 1.00 (s, 3H), 0.97 (s, 3H); MS (m/z ): 523.07 (M+H) ⁺ .

Example 16

2-chloro-5- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine

Use 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (intermediate 11, 40 mg, 0.132 mmol), 2-chloro-5-(p-amylaminomethyl) Benzoic acid (intermediate 5,200 mg, 0.743 mmol), ethylene dichloride (140 mg, 1.11 mmol), DMF (1 drop) and DIPEA (52 mg, 0.40 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared following the procedure described in Example 1 to give 15 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.5 (s, 1H), 9.1 (d, J = 7.8 Hz, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.05 (d, J =8.7 Hz, 1H), 7.71-7.60 (m, 4H), 7.48-7.38 (m, 4H), 6.64 (d, J = 5.1 Hz, 1H), 6.05 (br s, 1H), 4.49 (d, J = 6.0 Hz, 2H), 1.23 (s, 9H); MS [M+H] ⁺ : 556.19.

Example 17

3-chloro-6- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) picolinate Amides

Use 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (intermediate 11,100 mg, 0.327 mmol), 3-chloro-6-(p-amylaminomethyl) Pyridinecarboxylic acid (intermediate 3,180 mg, 0.66 mmol), ethylene dichloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (126 mg, 0.98 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared following the procedure described in Example 1 to afford 70 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 11.86 (s, 1H), 8.91 (d, J = 6.9 Hz, 1H), 8.81 (d, 1H), 8.35 (brt, 1H), 8.12 ( d, J = 7.8 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.80-7.70 (m, 5H), 7.47 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 4.8 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H), 1.16 (s, 9H); MS [M+H] ⁺ : 557.26.

Example 18

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine

Use 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (intermediate 11,100 mg, 0.327 mmol), 6-chloro-2-fluoro-3-(p-amylamine) Methyl)benzoic acid (intermediate 2,200 mg, 0.699 mmol), ethylene dichloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (126 mg, 0.98 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 40 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.77 (s, 1H), 8.79 (d, J = 8.7 Hz, 1H), 8.73 (d, 1H), 8.17 (brt, 1H), 8.08 ( d, J = 8.7 Hz, 1H), 7.78-7.67 (m, 5H), 7.41-7.35 (m, 2H), 6.83 (d, 1H), 4.32 (d, 2H), 1.14 (s, 9H); [M+H] ⁺ : 574.31.

Example 19

2-chloro-5- (aminomethyl pivaloyl XI) - N - (8 - ( (3- ( trifluoromethyl) phenyl) amino) quinolin-4-yl) benzoyl amine

To a solution of N ⁸ -(3-(trifluoromethyl)phenyl)quinolin-4,8-diamine (intermediate 12, 80 mg, 0.264 mmol) in DMF (2 mL) NaH (26 mg, 0.65 mmol, 60% in mineral oil) was added and the reaction mixture was stirred at 0-5 ° C for 30 min. Then a solution of 4-nitro-5-(pentamylaminomethyl)benzoic acid 4-nitrophenyl ester (intermediate 13,123 mg, 0.314 mmol) in DMF (1 mL) was added at 0 °C The reaction mixture was stirred for 2 hours at 0 ° C - room temperature in the reaction mixture. The reaction mixture was then quenched with water and EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 15 mg of title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.92 (s, 1H), 9.07 (s, 1H), 8.86 (d, J = 4.8 Hz, 1H), 8.21-8.18 (m, 2H), 7.80 -7.57 (m, 3H), 7.59-7.54 (m, 5H), 7.39 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 4.32 (d, J = 6.0 Hz, 2H), 1.19 (s, 9H); MS [M+H] ⁺ : 555.25.

Example 20

6-Chloro- N- (4-((4,4-difluorocyclohexyl)amino)quinazolin-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide amine

Use N ⁴ -(4,4-difluorocyclohexyl)quinazoline-4,8-diamine (intermediate 9,75 mg, 0.27 mmol), 6-chloro-2-fluoro-3-(penta Amidinomethyl)benzoic acid (intermediate 2,116 mg, 0.41 mmol), ethylene dichloride (78 mg, 0.62 mmol), DMF (1 drop) and DIPEA (105 mg, 0.81 mmol) of CH ₂ Cl _The title compound was prepared according to the procedure described in Example 1 (5 mL). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.40 (s, 1H), 8.69-8.66 (d, J = 7.8 Hz, 1H), 8.49 (s, 1H), 8.12-8.09 (m, 2H) , 7.53 (t, 1H), 7.40-7.32 (m, 2H), 4.28 (m, 3H), 2.09-1.98 (m, 6H), 1.73 (m, 2H), 1.12 (s, 9H); MS [M ] ⁺ :548.33.

Example 21

6-Chloro-2-fluoro- N- (4-((2-fluoro-5-(trifluoromethyl)phenyl)amino) quinazolin-8-yl)-3-(pentamylamine) Methyl)benzamide

Use N ⁴ -(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 14,100 mg, 0.31 mmol), 6-chloro-2-fluoro -3-(pentamethylene amino)benzoic acid (intermediate 2,178 mg, 0.62 mmol), ethylene dichloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93) mmol) of _{CH 2 Cl 2 (5 mL)} , in one of the title compound was prepared following the procedure example to give 12 mg of the title product. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.92 (s, 1H), 9.15 (d, 1H), 9.08 (d, 1H), 8.79 (s, 1H), 7.83 (s, 1H), 7.66 (m) , 2H), 7.40 (m, 2H), 4.50 (d, 2H), 1.23 (s, 9H); MS (m/z): 592.20 (M+H) ⁺ .

Example 22

6-Chloro- N- (4-((4,4-dimethylcyclohexyl)amino)quinazolin-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzene Guanamine

Use N ⁴ -(4,4-dimethylcyclohexyl)quinazoline-4,8-diamine (intermediate 15,100 mg, 0.37 mmol), 6-chloro-2-fluoro-3-(special) Pentamidine methyl)benzoic acid (intermediate 2,212 mg, 0.99 mmol), ethylene dichloride (188 mg, 1.49 mmol), DMF (1 drop) and DIPEA (143 mg, 1.11 mmol) of CH ₂ cl ₂ (5 mL), the title compound was prepared by following the procedures described in example 1 to give 10 mg of the title product. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.91 (s, 1H), 8.96 (d, 1H), 8.55 (s, 1H), 7.51-7.44 (m, 3H), 6.11 (br s, 1H), 5.67 (br s, 1H), 4.50 (d, 1H), 4.19 (m, 1H), 1.69-1.60 (m, 4H), 1.38-1.28 (m, 4H), 1.12 (s, 9H), 0.95 (s) , 3H), 0.92 (s, 3H); MS (m/z): 540.36 (M) ⁺ .

Example 23

(S) - N - (4- chloro-2-fluoro-3 - ((4 - ((3- (trifluoromethyl) phenyl) amino) quinazolin-8-yl) carbamoyl acyl) Benzyl)tetrahydrofuran-2-carboxamide

Stirring 4-chloro-2-fluoro-3-((4-((3-(trifluoromethyl)phenyl)amino))quinazolin-8-yl)amine carbamoyl)benzene at room temperature A solution of the tert-butyl carbamic acid ester (Intermediate 16, 80 mg, 0.135 mmol) in MeOH (2 mL) The reaction mixture was concentrated and the concentrate was dissolved in DMF (1 mL). DIPEA (87 mg, 0.675 mmol) and benzotriazol-1-yl-oxy-para-(dimethylamino)-hydrazine (119 mg, 0.27 mmol) and ( S) )-(-)-Tetrahydro-2-furic acid (24 mg, 0.203 mmol) was treated. The reaction mixture was stirred for 2 hours, then it was diluted with EtOAc and washed with H ₂ O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to give 35 mg of title product. ¹ H NMR (300 MHz, DMSO d ₆ ): δ 10.67 (s, 1H), 10.14 (s, 1H), 8.79 (d, 1H), 8.71 (s, 1H), 8.47 (brt, 1H), 8.37 (m, 2H), 8.25 (d, 1H), 7.73-7.65 (m, 2H), 7.50 (d, 1H), 7.39 (m, 2H), 4.33 (m, 3H), 3.94 (m, 1H), 3.80 (m, 1H), 2.14 (m, 1H), 1.84 (m, 3H); MS (m/z): 588.34 (M+H) ⁺ .

Example 24

6-Chloro- N- (4-((4,4-dimethylcyclohexyl)oxy)quinazolin-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzene Guanamine

Use 4-((4,4-dimethylcyclohexyl)oxy)quinazoline-8-amine (intermediate 10, 100 mg, 0.369 mmol), 6-chloro-2-fluoro-3- (special) Pentamidine methyl)benzoic acid (intermediate 2,211 mg, 0.738 mmol), ethylene dichloride (139 mg, 1.11 mmol), DMF (1 drop) and DIPEA (143 mg, 1.11 mmol) of CH ₂ cl ₂ (5 mL), the title compound was prepared by following the procedures described in example 1 to give 8 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.76 (s, 1H), 8.81 - 8.62 (m, 2H), 8.16 (brt, 1H), 7.95-7.92 (d, J = 8.4 Hz, 1H ), 7.74-7.69 (t, J = 8.4 Hz, 1H), 7.41-7.30 (m, 2H), 5.37 (m, 1H), 4.31-4.30 (d, J = 5.4 Hz, 2H), 1.94 (m, 2H), 1.82-1.78 (m, 2H), 1.52 (m, 2H), 1.34 (m, 2H), 1.14 (s, 9H), 1.00 (s, 3H), 0.67 (s, 3H); MS (m) /z): 541.14 (M ⁺ H) ⁺ .

Example 25

6-Chloro-2-fluoro- N- (4-((4-fluoro-3-(trifluoromethyl)phenyl)amino) quinazolin-8-yl)-3-(pentamylamine) Methyl)benzamide

Using N ⁴ -(4-fluoro-3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 17,100 mg, 0.31 mmol), 6-chloro-2-fluoro -3-(pentamylaminomethyl)benzoic acid (intermediate 2,178 mg, 0.62 mmol), ethylene dichloride (118 mg, 0.93 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93) mmol) of _{CH 2 Cl 2 (5 mL)} , in a procedure of a title compound was prepared following the example to give 16 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.62 (s, 1H), 10.15 (s, 1H), 8.8- 8.79 (d, J = 8.1 Hz, 1H), 8.69 (s, 1H), 8.33 -8.30 (m, 3H), 8.16 (br t, 1H), 7.75-7.69 (t, J = 8.4 Hz, 1H), 7.62 - 7.55 (d, J = 10.2 Hz, 1H), 7.42 - 7.34 (m, 2H), 4.32-4.30 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.28 (M+H) ⁺ .

Example 26

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( ((1 s, 4 s) -4- ( trifluoromethyl) cyclohexyl) oxy) quinoline Oxazoline-8-yl)benzamide

Use 4-(((1 s ,4 s )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline-8-amine (intermediate 20, 94 mg, 0.302 mmol), 6-chloro 2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,174 mg, 0.604 mmol), ethylene dichloride (115 mg, 0.91 mmol), DMF (1 drop) and DIPEA ( 117 mg, 0.91 mmol) of _{CH 2 Cl 2 (5 mL)} , the title compound was prepared by following the procedures described in example 1 to give 43 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 1077 (s, 1H), 8.81 (s, 1H), 8.79 (d, 1H), 8.15 (brt, 1H), 7.96-7.93 (d, J = 8.4 Hz, 1H), 7.73 (t, 1H), 7.40-7.32 (m, 2H), 5.63 (m, 1H), 4.31-4.29 (d, J = 5.4 Hz, 2H), 2.17 (m, 2H) , 1.78 (m, 6H), 1.13 (s, 9H); MS (m/z): 581.19 (M) ⁺ .

Example 27

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) oxy) quinoline Oxazoline-8-yl)benzamide

Use 4-((( r , 4r )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline-8-amine (intermediate 21, 130 mg, 0.452 mmol), 6-chloro 2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,85 mg, 0.678 mmol), ethylene dichloride (129 mg, 1.02 mmol), DMF (1 drop) and DIPEA ( 175 mg, 1.36 mmol) of _{CH 2 Cl 2 (8 mL)} , the title compound was prepared by following the procedures described in example 1 to give 75 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.78 (s, 1H), 8.83 (s, 1H), 8.79 (s, 1H), 8.16 (m, 1H), 7.91 - 7.89 (d, J = 8.4 Hz, 1H), 7.71 (t, 1H), 7.38-7.33 (m, 2H), 5.33 (m, 1H), 4.32-4.30 (d, J = 5.1 Hz, 2H), 2.28 (m, 3H), 1.99 (m, 2H), 1.64-1.53 (m, 4H), 1.15 (s, 9H); MS (m/z): 581.45 (M) ⁺ .

Example 28

6-Chloro-2-fluoro- N- (4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinazolin-8-yl)-3-(pentamylaminomethyl) Benzylamine

Use 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinazoline-8-amine (intermediate 22, 300 mg, 0.93 mmol), 6-chloro-2-fluoro-3- (p-amylaminomethyl)benzoic acid (intermediate 2,322 mg, 1.12 mmol), ethylene dichloride (212 mg, 1.68 mmol), DMF (1 drop) and DIPEA (360 mg, 2.79 mmol) _{CH 2 Cl 2 (10 mL)} , the title compound was prepared by following the procedures described in example 1 to give 75 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.97 (s, 1H), 8.92-8.90 (d, J = 7.2 Hz, 1H), 8.81 (s, 1H), 8.19-8.10 (m, 3H) , 7.89-7.84 (m, 2H), 7.77-7.71 (t, J = 9.9 Hz, 1H), 7.40-7.32 (m, 2H), 4.31-4.29 (d, J = 6.0 Hz, 2H), 1.13 (s , 9H); MS (m/z): 593.31 (M+H) ⁺ .

Example 29

6-Chloro-2-fluoro- N- (4-((2-fluoro-4-(trifluoromethyl)phenyl)amino) quinazolin-8-yl)-3-(pentamylamine) Methyl)benzamide

Use N ⁴ -(2-fluoro-4-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 23,230 mg, 0.71 mmol), 6-chloro-2-fluoro -3-(pentamethylene amino)benzoic acid (intermediate 2,245 mg, 0.85 mmol), ethylene dichloride (161 mg, 1.28 mmol), DMF (1 drop) and DIPEA (275 mg, 2.13) mmol) of _{CH 2 Cl 2 (8 mL)} , the title compound was prepared by following the procedures described in example 1 to give 70 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.63 (s, 1H), 10.22 (s, 1H), 8.8- 8.79 (d, J = 8.1 Hz, 1H), 8.59 (s, 1H), 8.28 -8.25 (d, J = 9.0 Hz, 1H), 8.16 (m, 1H), 7.89-7.83 (m, 2H), 7.75-7.67 (m, 2H), 7.42-7.34 (m, 2H), 4.32-4.30 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.33 (M+H) ⁺ .

Example 30

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( (6- ( trifluoromethyl) pyridin-3-yl) amino) quinazolin-8 Benzomamide

Using N ⁴ -(6-(trifluoromethyl)pyridin-3-yl)quinazoline-4,8-diamine (intermediate 24, 150 mg, 0.49 mmol), 6-chloro-2-fluoro- 3-(Pentamylaminomethyl)benzoic acid (intermediate 2,170 mg, 0.59 mmol), ethylene dichloride (112 mg, 0.89 mmol), DMF (1 drop) and DIPEA (190 mg, 1.47 mmol) ) of _{CH 2 Cl 2 (5 mL)} , the title compound was prepared by following the procedures described in example 1 to give 25 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.68 (s, 1H), 10.36 (s, 1H), 9.23 (s, 1H), 8.83-8.80 (d, J = 7.8 Hz, 1H), 8.75 (s, 1H), 8.69-8.65 (d, J = 9.6 Hz, 1H), 8.37-8.34 (d, J = 8.7 Hz, 1H), 8.16 (br t, 1H), 7.97-7.94 (d, J = 8.7 Hz, 1H), 7.79 (t, 1H), 7.41-7.33 (m, 2H), 4.31-4.29 (d, J = 5.4 Hz, 2H), 1.13 (s, 9H); MS (m/z): 575.18(M+H) ⁺ .

Example 31

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( (3- ( trifluoromethyl) phenyl) amino) quinolin-8-yl) benzoate Guanamine

Using N ⁴ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine (intermediate 25, 100 mg, 0.33 mmol), 6-chloro-2-fluoro-3- (spec Pentamidine methyl)benzoic acid (intermediate 2,190 mg, 0.66 mmol), ethylene dichloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (128 mg, 0.99 mmol) of CH ₂ cl ₂ (6 mL), the title compound was prepared by following the procedures described in example 1 to give 20 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.62 (s, 1H), 9.35 (s, 1H), 8.73-8.71 (d, J = 7.2 Hz, 1H), 8.52 (d, 1H), 8.17 (m, 2H), 7.71-7.62 (m, 4H), 7.48-7.36 (m, 3H), 7.14 (m, 1H), 4.31 (d, 2H), 1.14 (s, 9H); MS (m/z ): 573.36 (M+H) ⁺ .

Example 32

6-Chloro- N- (4-((4,4-dimethylcyclohexyl)amino)-2-(trifluoromethyl)quinazolin-8-yl)-2-fluoro-3-( Pentamidine methyl)benzamide

Using N ⁴ -(4,4-dimethylcyclohexyl)-2-(trifluoromethyl)quinazoline-4,8-diamine (intermediate 26, 100 mg, 0.295 mmol), 6-chloro 2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,127 mg, 0.443 mmol), ethylene dichloride (84 mg, 0.66 mmol), DMF (1 drop) and DIPEA ( 115 mg, 0.89 mmol) of _{CH 2 Cl 2 (3 mL)} , the title compound was prepared by following the procedures described in example 1 to give 35 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.30 (s, 1H), 8.67-8.65 (d, J = 7.2 Hz, 1H), 8.59-8.56 (d, J = 8.1 Hz, 1H), 8.22 -8.16 (m, 2H), 7.74 - 7.68 (t, J = 8.4 Hz, 1H), 7.45-7.33 (m, 2H), 4.32-4.30 (d, J = 5.4 Hz, 2H), 4.14 (m, 1H) ), 1.76-1.66 (m, 4H), 1.43-1.24 (m, 4H), 1.14 (s, 9H), 0.99 (s, 3H), 0.95 (s, 3H); MS (m/z): 608.38 ( M+H) ⁺ .

Example 33

6-Chloro-2-fluoro- N- (2-methyl-4-((3-(trifluoromethyl)phenyl)amino)quinazolin-8-yl)-3-(p-amylamine) Methyl benzyl guanamine

Using 2-methyl- N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 27, 100 mg, 0.314 mmol), 6-chloro-2- Fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,181 mg, 0.629 mmol), ethylene dichloride (119 mg, 0.94 mmol), DMF (1 drop) and DIPEA (122 mg, 0.94 mmol) of _{CH 2 Cl 2 (4 mL)} , following the example 1 the title compound was prepared in the procedure to give 17 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.42 (s, 1H), 10.04 (s, 1H), 8.77 (d, 1H), 8.43 (s, 1H), 8.31 (m 2H), 8.16 ( m,1H), 7.64 (m, 2H), 7.48-7.36 (m, 3H), 4.31 (d, 2H), 2.58 (s, 3H), 1.14 (s, 9H); MS (m/z): 588.31 (M+H) ⁺ .

Example 34

2-chloro-6-fluoro- N- (4-((2-fluoro-5-(trifluoromethyl)phenyl)amino) quinazolin-8-yl)benzamide

Use N ⁴ -(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 14, 60 mg, 0.18 mmol), 6-chloro-2-fluoro Benzoic acid (48 mg, 0.27 mmol), ethylene dichloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) in CH ₂ Cl ₂ (2 mL) The title compound was prepared as described to give 45 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.69 (s, 1H), 10.16 (s, 1H), 8.80 (d, J = 7.5 Hz, 1H), 8.57 (s, 1H), 8.23 (d) , J = 8.4 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.63 - 7.51 (m, 2H), 7.44 - 7.36 (m, 2H); MS ( m/z): 479.30 (M+H) ⁺ .

Example 35

6-Chloro- N- (1-((4,4-dimethylcyclohexyl)oxy)isoquinolin-5-yl)-2-fluoro-3-(pentamylamino)benzamide Guanamine

Use 1-((4,4-dimethylcyclohexyl)oxy)isoquinolin-5-amine (intermediate 28, 70 mg, 0.25 mmol), 6-chloro-2-fluoro-3- (special) Pentamidine methyl)benzoic acid (intermediate 2,89 mg, 0.31 mmol), ethylene dichloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (97 mg, 0.75 mmol) of CH ₂ cl ₂ (3 mL), the title compound was prepared by following the procedures described in example 1 to give 45 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.89 (s, 1H), 8.19 (t, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 5.7 Hz, 1H) ), 7.95 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 6.0 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 5.28 (m, 1H), 4.34 (d, J = 5.4 Hz, 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.53 (m, 2H), 1.34 (m) , 2H), 1.15 (s, 9H), 1.00 (s, 3H), 0.97 (s, 3H); MS (m/z): 540.10 (M+H) ⁺ .

Example 36

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (1 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) amino) iso Quinoline-5-yl)benzamide

Using N ¹ -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)isoquinoline-1,5-diamine (intermediate 29, 63 mg, 0.20 mmol), 6-chloro 2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,70 mg, 0.24 mmol), ethylene dichloride (45 mg, 0.36 mmol), DMF (1 drop) and DIPEA ( 77 mg, 0.60 mmol) of _{CH 2 Cl 2 (2 mL)} , the title compound was prepared by following the procedures described in example 1 to give 30 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.72 (s, 1H), 8.25-8.22 (m, 2H), 7.90 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 7.5 Hz , 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H) ), 7.05 (d, J = 6.0 Hz, 1H), 4.33 (d, J = 5.4 Hz, 2H), 4.11 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.96 (m) , 2H), 1.44 (m, 4H), 1.14 (s, 9H); MS (m/z): 579.40 (M) ⁺ .

Example 37

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) amino) quinolin Oxazoline-8-yl)benzamide

Using N ⁴ -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)quinazoline-4,8-diamine (intermediate 30, 188 mg, 0.60 mmol), 6-chloro 2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,311 mg, 1.09 mmol), ethylene dichloride (207 mg, 1.64 mmol), DMF (1 drop) and DIPEA ( 232 mg, 1.80 mmol) of _{CH 2 Cl 2 (7 mL)} , the title compound was prepared by following the procedures described in example 1 to give 30 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.38 (s, 1H), 8.66 (d, 1H), 8.46 (s, 1H), 8.13 - 8.06 (m, 3H), 7.52 (t, 1H) , 7.37 (m, 2H), 4.28 (d, J = 6.0 Hz, 2H), 4.17 (m, 1H), 2.31 (m, 1H), 2.18 (m, 2H), 1.82 (m, 2H), 1.42 ( m, 4H), 1.12 (s, 9H); MS (m/z): 580.42 (M+H) ⁺ .

Example 38

2-chloro-5- (aminomethyl pivaloyl XI) - N - (1 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) oxy) isoquinolin-5 -yl)benzamide

Use 1-(((1 r , 4 r )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-5-amine (intermediate 33, 130 mg, 0.41 mmol), 2-chloro -5-(pentamylaminomethyl)benzoic acid (intermediate 5,169 mg, 0.62 mmol), ethylene dichloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (159 mg, 1.23) mmol) of _{CH 2 Cl 2 (5 mL)} , in a procedure of a title compound was prepared following the example to obtain 120 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.61 (s, 1H), 8.17 (m, 1H), 8.05 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 6.3 Hz, 1H) ), 7.92 (d, 1H), 7.63 (m, 1H), 7.50 (m, 3H), 7.34 (d, J = 7.8 Hz, 1H), 5.19 (m, 1H), 4.29 (d, 1H), 2.38 (m, 1H), 2.25 (m, 2H), 1.95 (m, 2H), 1.61-1.46 (m, 4H), 1.12 (s, 9H); MS (m/z): 562.10 (M+H) ⁺ .

Example 39

2-chloro-5- (aminomethyl pivaloyl XI) - N - (4 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) oxy) quinazoline -8 -yl)benzamide

Use 4-((( r , 4r )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline-8-amine (intermediate 21, 60 mg, 0.19 mmol), 2-chloro -5-(pentamethylene amino)benzoic acid (intermediate 5,100 mg, 0.38 mmol), ethylene dichloride (72 mg, 0.57 mmol), DMF (1 drop) and DIPEA (74 mg, 0.57) mmol) of _{CH 2 Cl 2 (2 mL)} , the title compound was prepared by following the procedures described in example 1 to give 20 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.23 (s, 1H), 8.80 (m, 2H), 8.16 (t, 1H), 7.83 (d, 1H), 7.69 (t, 1H), 7.58 -7.52 (m, 2H), 7.38 (d, 1H), 5.30 (m, 1H), 4.27 (d, 2H), 2.38 (m, 1H), 2.26 (m, 2H), 1.96 (m, 2H), 1.62-1.50 (m, 4H), 1.11 (s, 9H); MS (m/z): 563.09 (M+H) ⁺ .

Example 40

6-chloro-2-fluoro- N- (4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinolin-8-yl)-3-(pentamylaminomethyl)benzene Formamide

Using 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinolin-8-amine (intermediate 35, 100 mg, 0.31 mmol), 6-chloro-2-fluoro-3-( CH of p-amylaminomethyl)benzoic acid (intermediate 2, 133 mg, 0.46 mmol), ethylene dichloride (187 mg, 0.69 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93 mmol) ₂ Cl ₂ (4 mL), the title compound was prepared by following the procedures described in example 1 to give 80 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.74 (s, 1H), 8.78 (d, J = 7.8 Hz, 1H), 8.70 (d, J = 5.4 Hz, 1H), 8.11 - 8.05 (m) , 3H), 7.83-7.71 (m, 3H), 7.41-7.30 (m, 2H), 6.83 (d, J = 4.8 Hz, 1H), 4.29 (d, J = 5.4 Hz, 2H), 1.12 (s, 9H); MS (m/z): 592.33 (M+H) ⁺ .

Example 41

2-Chloro- N- (1-(2-fluoro-5-(trifluoromethyl)phenoxy)isoquinolin-5-yl)-5-(pentamylaminomethyl)benzamide

Use 1-(2-fluoro-5-(trifluoromethyl)phenoxy)isoquinolin-5-amine (intermediate 36, 80 mg, 0.24 mmol), 2-chloro-5-(tepentaquinone) Aminomethyl)benzoic acid (intermediate 5,134 mg, 0.49 mmol), ethylene dichloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) of CH ₂ Cl ₂ The title compound was prepared (5 mL ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.77 (s, 1H), 8.32 (d, 1H), 8.11 (t, 1H), 8.09 (d, 1H), 8.00-7.96 (m, 2H) , 7.75-7.69 (m, 4H), 7.55 (m, 2H), 7.38 (d, 1H), 4.32 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H).

Example 42

6-Chloro-2-fluoro- N- (7-methyl-4-((3-(trifluoromethyl)phenyl)amino)quinazolin-8-yl)-3-(p-amylamine) Methyl benzyl guanamine

Using 7-methyl- N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (intermediate 37, 140 mg, 0.44 mmol), 6-chloro-2- Fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,163 mg, 0.57 mmol), ethylene dichloride (108 mg, 0.86 mmol), DMF (1 drop) and DIPEA (170 mg, 1.32 mmol) of _{CH 2 Cl 2 (5 mL)} , the title compound was prepared by following the procedures described in example 1 to give 25 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.71 (s, 1H), 10.03 (s, 1H), 8.72 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.35 (s) , 1H), 8.27 (d, J = 9.3 Hz, 1H), 8.19 (t, 1H), 7.66-7.63 (m, 2H), 7.46 (d, J = 6.9 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.31 (t, J 8.1 Hz, 1H), 4.33 (d, J = 5.4 Hz, 2H), 2.50 (s, 3H), 1.15 (s, 9H); MS (m/z): 588.23(M) ⁺ .

Example 43

6-Chloro- N- (4-ethoxyquinazolin-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide

Use 4-ethoxyquinazoline-8-amine (intermediate 38, 140 mg, 0.80 mmol), 6-chloro-2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate) 2,323 mg, 1.12 mmol), ethylene dichloride (141 mg, 1.12 mmol), DMF (1 drop) and DIPEA (310 mg, 2.40 mmol) in CH ₂ Cl ₂ (4 mL) The title compound was prepared to give 65 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.75 (s, 1H), 8.79 (m, 2H), 8.13 (t, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.69 (t , 1H), 7.36-7.31 (m, 2H), 4.62 (m, 2H), 4.29 (d, J = 6.0 Hz, 2H), 1.44 (t, J = 7.5 Hz, 3H), 1.12 (s, 9H) MS (m/z): 459.20 (M+H) ⁺ .

Example 44

2-Chloro- N- (1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)-5-(p-amylaminomethyl)benzene Formamide

Using N ¹ -(2-fluoro-4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (intermediate 39, 80 mg, 0.24 mmol), 2-chloro-5- ( CH of p-amylaminomethyl)benzoic acid (intermediate 5,134 mg, 0.49 mmol), ethylene dichloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) ₂ Cl ₂ (5 mL), the title compound was prepared by following the procedures described in example 1 to give 25 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.62 (s, 1H), 9.38 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.21 (t, 1H), 8.00-7.93 (m, 2H), 7.88 (t, J = 7.5 Hz, 1H), 7.71 (d, J = 9.3 Hz, 2H), 7.60-7.53 (m, 3H), 7.44 (d, J = 5.7 Hz, 1H) , 7.36 (d, J = 9.0 Hz, 1H), 4.32 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 573.29 (M+H) ⁺ .

Example 45

2-chloro-5- (aminomethyl pivaloyl XI) - N - (1 - ( (4- ( trifluoromethyl) phenyl) amino) isoquinolin-5-yl) benzoyl amine

Using N ¹ -(4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (intermediate 40, 100 mg, 0.33 mmol), 2-chloro-5-(p-amylamine Methyl)benzoic acid (intermediate 5,177 mg, 0.66 mmol), ethylene dichloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (128 mg, 0.99 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 40 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.62 (s, 1H), 9.59 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.21 (t, 1H), 8.12 (m) , 3H), 7.94 (d, 1H), 7.68-7.65 (m, 3H), 7.53 (m, 2H), 7.47 (d, J = 6.0 Hz, 1H), 7.38 (d, 1H), 4.32 (d, 2H), 1.15 (s, 9H); MS (m/z): 555.30 (M+H) ⁺ .

Example 46

2-chloro-5- (aminomethyl pivaloyl XI) - N - (1- (4- ( trifluoromethyl) phenoxy) isoquinolin-5-yl) benzoyl amine

Use 1-(4-(trifluoromethyl)phenoxy)isoquinolin-5-amine (intermediate 41, 100 mg, 0.32 mmol), 2-chloro-5-(p-amylaminomethyl) Benzoic acid (intermediate 5,177 mg, 0.65 mmol), ethylene dichloride (123 mg, 0.98 mmol), DMF (1 drop) and DIPEA (124 mg, 0.96 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared following the procedure described in Example 1 to afford 33 mg title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.76 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.21 (t, 1H), 8.08 (d, J = 6.9 Hz, 1H) ), 7.99 (d, J = 6.0 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 6.3 Hz, 1H), 7.54 (m, 4H), 7.37 (d, J) = 8.4 Hz, 2H), 4.32 (d, J = 5.7 Hz, 2H), 1.14 (s, 9H); MS (m/z): 556.29 (M+H) ⁺ .

Example 47

2-chloro-5- (aminomethyl pivaloyl XI) - N - (1 - ( ((1 s, 4 s) -4- ( trifluoromethyl) cyclohexyl) oxy) isoquinolin-5 -yl)benzamide

Using 1-(((1 s , 4 s )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-5-amine (Intermediate 34, 40 mg, 0.12 mmol), 2-chloro -5-(pentamylaminomethyl)benzoic acid (intermediate 5, 52 mg, 0.19 mmol), ethylene dichloride (37 mg, 0.29 mmol), DMF (1 drop) and DIPEA (46 mg, 0.36) mmol) of _{CH 2 Cl 2 (2 mL)} , the title compound was prepared by following the procedures described in example 1 to give 17 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.64 (s, 1H), 8.20 (t, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 6.3 Hz, 1H) ), 7.96 (d, J = 7.2 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.56-7.51 (m, 3H), 7.36 (d, J = 7.8 Hz, 1H), 5.55 (m) , 1H), 4.32 (d, J = 5.4 Hz, 2H), 2.42 (m, 1H), 2.26 (m, 2H), 2.17 (m, 2H), 1.76-1.73 (m, 4H), 1.14 (s, 9H); MS (m/z): 562.11 (M) ⁺ .

Example 48

2-Chloro- N- (1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-yl)-5-(pentamylaminomethyl)benzamide

Use 1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (intermediate 42, 80 mg, 0.24 mmol), 2-chloro-5- (p-pentamidine) Aminomethyl)benzoic acid (intermediate 5,134 mg, 0.49 mmol), ethylene dichloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) of CH ₂ Cl ₂ The title compound was prepared (5 mL), m. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.75 (s, 1H), 8.30 (d, 1H), 8.21 (t, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.98 (d) , J = 6.3 Hz, 1H), 7.82 - 7.55 (m, 7H), 7.37 (d, J = 8.4 Hz, 1H), 4.32 ( J = 5.4 Hz, 2H), 1.14 (s, 9H); MS (m /z): 574.22 (M ⁺ H) ⁺ .

Example 49

6-Chloro-2-methoxy-3- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoate Guanamine

Use 4-(3-(trifluoromethyl)phenoxy)quinazoline-8-amine (intermediate 8, 60 mg, 0.19 mmol), 6-chloro-2-methoxy-3-(spec Pentamidine methyl)benzoic acid (intermediate 43, 88 mg, 0.29 mmol), ethylene dichloride (55 mg, 0.44 mmol), DMF (1 drop) and DIPEA (74 mg, 0.57 mmol) of CH ₂ cl _{2 (2} mL), the title compound was prepared by following the procedures described in example 1 to give 36 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.49 (s, 1H), 8.92 (d, J = 7.8 Hz, 1H), 8.77 (s, 1H), 8.17-8.11 (m, 2H), 7.86 (m, 2H), 7.74 (m, 3H), 7.30 (m, 2H), 4.29 (d, 2H), 3.84 (s, 3H), 1.15 (s, 9H); MS (m/z): 587.17 ( M+H) ⁺ .

Example 50

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (1 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) oxy) iso Quinoline-5-yl)benzamide

Use 1-((( r , 4r )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-5-amine (intermediate 33, 80 mg, 0.25 mmol), 6-chloro 2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2,111 mg, 0.38 mmol), ethylene dichloride (72 mg, 0.57 mmol), DMF (1 drop) and DIPEA ( 97 mg, 0.75 mmol) of _{CH 2 Cl 2 (5 mL)} , followed in the procedure of example 1 the title compound was prepared to give 35 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.90 (s, 1H), 8.19 (t, J = 6.0 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 6.6 Hz, 1H), 7.96 (d, J = 6.9 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.51 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 5.22 (m, 1H), 4.34 (d, J = 5.1 Hz, 2H), 2.41 (m, 1H), 2.27 (m, 2H), 2.01-1.97 (m, 2H), 1.64-1.44 (m, 4H), 1.15 (s, 9H); MS (m/z): 580.12 (M+H) ⁺ .

Example 51

6-Chloro-2-fluoro- N- (4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinolin-8-yl)-3-(pentamylaminomethyl)benzene Formamide

Using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinoline-8-amine (Intermediate 44, 60 mg, 0.18 mmol), 6-chloro-2-fluoro-3-( CH of p-amylaminomethyl)benzoic acid (intermediate 2, 80 mg, 0.27 mmol), ethylene dichloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) ₂ Cl _{2 (2} mL), the title compound was prepared by following the procedures described in example 1 to give 35 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.75 (s, 1H), 8.79 (d, J = 7.5 Hz, 1H), 8.71 (d, J = 5.1 Hz, 1H), 8.16 (t, 1H) ), 8.09 (d, J = 8.7 Hz, 1H), 7.88 (m, 1H), 7.75-7.70 (m, 3H), 7.38 (m, 2H), 6.83 (d, J = 5.4 Hz, 1H), 4.32 (d, J = 5.1 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.29 (M+H) ⁺ .

Example 52

6-Chloro-2-fluoro- N- (4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazolin-8-yl)-3-(pentamylaminomethyl) Benzylamine

Using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate 45, 60 mg, 0.18 mmol), 6-chloro-2-fluoro-3- (p-amylaminomethyl)benzoic acid (intermediate 2, 80 mg, 0.27 mmol), ethylene dichloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) _{CH 2 Cl 2 (2 mL)} , the title compound was prepared by following the procedures described in example 1 to give 42 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.93 (s, 1H), 8.91 (d, J = 7.8 Hz, 1H), 8.80 (s, 1H), 8.17 (d, J = 7.2 Hz, 2H ), 7.96 (t, 1H), 7.85 (m, 2H), 7.69 (t, J = 9.6 Hz, 1H), 7.37 (m, 2H), 4.31 (d, J = 5.4 Hz, 2H), 1.14 (s) , 9H); MS (m/z): 593.10 (M+H) ⁺ .

Example 53

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4- (4- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine

Using 4-(4-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate 46, 126 mg, 0.44 mmol), 6-chloro-2-fluoro-3-(p-amylamine) Methyl)benzoic acid (intermediate 2,142 mg, 0.49 mmol), ethylene dichloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (170 mg, 1.32 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 30 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.78 (s, 1H), 8.80-8.75 (m, 2H), 8.16 (t, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 ( d, J = 7.2 Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 4.31 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 574.26 ( M+H) ⁺ .

Example 54

6-Chloro- N- (4-((4,4-dimethylcyclohexyl)amino)-2-methylquinazolin-8-yl)-2-fluoro-3-(pentamylamine) Methyl)benzamide

Using N ⁴ -(4,4-dimethylcyclohexyl)-2-methylquinazoline-4,8-diamine (intermediate 47, 180 mg, 0.63 mmol), 6-chloro-2-fluoro -3-(pentamethylene amino)benzoic acid (intermediate 2,271 mg, 0.95 mmol), ethylene dichloride (180 mg, 1.43 mmol), DMF (1 drop) and DIPEA (244 mg, 1.89) mmol) of _{CH 2 Cl 2 (8 mL)} , the title compound was prepared by following the procedures described in example 1 to give 25 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.18 (s, 1H), 8.66 (d, J = 7.8 Hz, 1H), 8.14 (t, 1H), 8.02 (d, J = 8.1 Hz, 1H) ), 7.93 (d, 1H), 7.43 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 4.31 (d, 2H), 4.17 (m, 1H), 2.44 (s, 3H), 1.72 (m, 2H), 1.64-1.60 (m, 2H), 1.41-1.28 (m, 4H), 1.14 (s, 9H), 0.98 (s, 3H), 0.94 (s, 3H); MS (m/z ): 554.35 (M+H) ⁺ .

Example 55

6-Chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (quinolin-8-yl) benzoyl amine

Use quinoline-8-amine (intermediate 48, 50 mg, 0.34 mmol), 6-chloro-2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2, 119 mg, 0.41) mmol), oxalyl acyl chloride (78 mg, 0.62 mmol), DMF (1 drop) and DIPEA (132 mg, 1.02 mmol) of _{CH 2 Cl 2 (5 mL)} , followed example 1. the title compound was prepared the procedure To give 15 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.73 (s, 1H), 8.91 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 8.48 (d, 1H), 8.16 (t) , 1H), 7.78 (d, 1H), 7.67 (t, J = 7.2 Hz, 2H), 7.40 (m, 2H), 4.32 (d, 2H), 1.14 (s, 9H); MS (m/z) :414.23(M+H) ⁺ .

Example 56

6-Chloro-2-fluoro- N- (2-methyl-4-(3-(trifluoromethyl)phenoxy)quinazolin-8-yl)-3-(p-amylaminomethyl) Benzoguanamine

Using 2-methyl-4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (intermediate 49, 150 mg, 0.47 mmol), 6-chloro-2-fluoro-3 -(p-amylaminomethyl)benzoic acid (intermediate 2,200 mg, 0.71 mmol), ethylene dichloride (135 mg, 1.07 mmol), DMF (1 drop) and DIPEA (182 mg, 1.41 mmol) the _{CH 2 Cl 2 (6 mL)} , following the procedure of example 1 the title compound was prepared to give 38 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.65 (s, 1H), 8.99 (d, 1H), 8.12 (m, 2H), 7.84-7.74 (m, 4H), 7.41 (m, 2H) , 4.32 (d, 2H), 2.50 (s, 3H), 1.14 (s, 9H); MS (m/z): 589.20 (M+H) ⁺ .

Example 57

6-Chloro-2-fluoro- N- (4-(isopropylamino)-2-methylquinazoline-8..yl)-3-(pentamylaminomethyl)benzamide

Using N ⁴ -isopropyl-2-methylquinazolin-4,8-diamine (intermediate 50, 30 mg, 0.14 mmol), 6-chloro-2-fluoro-3-(pentamylamine) Methyl)benzoic acid (intermediate 2, 60 mg, 0.20 mmol), ethylene dichloride (38 mg, 0.30 mmol), DMF (1 drop) and DIPEA (77 mg, 0.60 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 23 mg title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.16 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H), 8.12-8.01 (t, J = 8.4 Hz, 1H), 7.92 (d) , J = 7.6 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.41-7.35 (m, 3H), 4.57-4.52 (m, 1H), 4.30 (d, J = 5.6 Hz, 2H) , 2.44 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.13 (s, 9H); MS (m/z): 486.27 (M+H) ⁺ .

Example 58

6-Chloro-2-fluoro- N- (2-methyl-4-(N-morpholinyl)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide

Using 2-methyl-4-(N-morpholinyl)quinazolin-8-amine (intermediate 51, 100 mg, 0.41 mmol), 6-chloro-2-fluoro-3-(pivalamylamine) Methyl)benzoic acid (intermediate 2,176 mg, 0.61 mmol), ethylene dichloride (115 mg, 0.92 mmol), DMF (1 drop) and DIPEA (159 mg, 1.23 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 53 mg of the title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.36 (s, 1H), 8.69 (d, J = 7.6 Hz, 1H), 8.14-8.11 (t, J = 5.7 Hz, 1H), 7.76-7.74 (d, J = 8.4 Hz, 1H), 7.50-7.46 (t, J = 8.1 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.37-7.33 (t, J = 8.0 Hz, 1H) , 4.30 (d, J = 5.7 Hz, 2H), 3.77 (d, J = 4.7 Hz, 2H), 3.73 (d, J = 4.6 Hz, 2H), 3.30 (s, 3H), 1.13 (s, 9H) ;MS (m/z): 514.29 (M+H) ⁺ .

Example 59

6-Chloro-2-fluoro- N- (4-isopropoxyquinazolin-8-yl)-3-(pentamylaminomethyl)benzamide

Using 4-isopropoxy quinazolin-8-amine (intermediate 52, 100 mg, 0.49 mmol), 6-chloro-2-fluoro-3-(pentamylaminomethyl)benzoic acid (middle) 2,184 mg, 0.64 mmol), ethylene dichloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (571 mg, 1.48 mmol) in CH ₂ Cl ₂ (5 mL). The title compound was prepared to give 40 mg of the title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.73 (s, 1H), 8.78 (s, 1H), 8.76 (s, 1H), 8.15-8.12 (t, J = 5.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.69-7.65 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.32 - 7.28 (t, J = 8.0 Hz, 1H) , 5.60-5.54 (m, 1H), 4.28 (d, J = 6.0 Hz, 2H), 1.42 (d, J = 6.0 Hz, 6H), 1.11 (s, 9H); MS (m/z): 473.11 ( M+H) ⁺ .

Example 60

6-Chloro- N- (4-((4,4-difluorocyclohexyl)amino)-2-methylquinazolin-8-yl)-2-fluoro-3-(pentamylamino) Benzomamide

Using N ⁴ -(4,4-difluorocyclohexyl)-2-methylquinazolin-4,8-diamine (intermediate 53, 100 mg, 0.342 mmol), 6-chloro-2-fluoro- 3-(Pentamethylene amino)benzoic acid (intermediate 2,147 mg, 0.513 mmol), ethylene dichloride (97 mg, 0.77 mmol), DMF (1 drop) and DIPEA (132 mg, 1.026 mmol) ) of _{CH 2 Cl 2 (3 mL)} , the title compound was prepared by following the procedures described in example 1 to give 46 mg of the title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.25 (s, 1H), 8.68 (d, J = 7.6 Hz, 1H), 8.18-8.15 (t, J = 5.8 Hz, 1H), 8.06-8.04 (d, J = 8.4 Hz, 1H), 7.97-7.95 (d, J = 7.6 Hz, 1H), 7.48-7.42 (m, 2H), 7.38-7.36 (d, J = 8.0 Hz, 1H), 4.44 ( m,1H), 4.30 (d, J = 5.6 Hz, 2H), 2.46 (s, 3H), 2.10 - 1.99 (m, 6H), 1.76-1.73 (m, 2H), 1.14 (s, 9H); (m/z): 562.32 (M+H) ⁺ .

Example 61

6-Chloro- N- (4-(dimethylamino)quinazolin-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide

Using N ⁴ , N ⁴ -dimethylquinazoline-4,8-diamine (intermediate 54,100 mg, 0.53 mmol), 6-chloro-2-fluoro-3-(pentamylamine) Benzoic acid (intermediate 2,184 mg, 0.64 mmol), ethylene dichloride (203 mg, 1.6 mmol), DMF (1 drop) and DIPEA (344 mg, 2.67 mmol) of CH ₂ Cl ₂ (2 mL) The title compound was prepared following the procedure described in Example 1 to afford 46 mg title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.43 (s, 1H), 8.70-8.68 (d, J = 7.6 Hz, 1H), 8.50 (s, 1H), 8.14-8.11 (t, J = 5.6 Hz, 1H), 7.95-7.93 (d, J = 8.4 Hz, 1H), 7.51-7.47 (t, J = 8.0 Hz, 1H), 7.41-7.39 (d, J = 8.4 Hz, 1H), 7.36 -7.32 (t, J = 8.0 Hz, 1H), 4.31-4.29 (d, J = 5.6 Hz, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 1.13 (s, 9H); MS ( m/z): 458.22 (M+H) ⁺ .

Example 62

N- (4-(Tertiary butylamino)quinazolin-8-yl)-6-chloro-2-fluoro-3-(pentamylaminomethyl)benzamide

Using N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-(pentamylamine) Benzoic acid (intermediate 2, 146 mg, 0.51 mmol), ethylene dichloride (126 mg, 0.99 mmol), DMF (1 drop) and DIPEA (132 mg, 1.03 mmol) in CH ₂ Cl ₂ (3 mL) The title compound was prepared following the procedure described in Example 1 to give 30 mg of the title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.39 (s, 1H), 8.69-8.67 (d, J = 7.4 Hz, 1H), 8.51 (s, 1H), 8.18-8.16 (m, 2H) , 7.54 - 7.50 (t, J = 8.0 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.37 - 7.33 (t, J = 8.0 Hz, 1H), 4.32-4.30 (d, J = 6.0 Hz, 2H ), 1.56 (s, 9H), 1.14 (s, 9H); MS (m/z): 486.25 (M+H) ⁺ .

Example 63

6-Chloro- N- (4-ethoxyquinolin-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide

Use 4-ethoxyquinolin-8-amine (intermediate 56, 80 mg, 0.425 mmol), 6-chloro-2-fluoro-3-(pentamylaminomethyl)benzoic acid (intermediate 2 , 159 mg, 0.553 mmol), oxalyl chloride (162 mg, 1.27 mmol), DMF (1 drop) and DIPEA (219 mg, 1.7 mmol) in CH ₂ Cl ₂ (2 mL), as described in Example 1. Procedure The title compound was prepared to give 46 mg of the title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.59 (s, 1H), 8.81 - 8.68 (m, 2H), 8.13 (t, 1H), 7.93 - 7.90 (dd, J = 1.2, 8.4 Hz, 1H), 7.61-7.57 (t, J = 8.0 Hz, 1H), 7.42-7.40 (d, J = 8.4 Hz, 1H), 7.36-7.23 (t, J = 8.0 Hz, 1H), 7.12-7.11 (d , J = 5.2 Hz, 1H), 4.35-4.29 (m, 4H), 1.50-1.47 (t, J = 7.2 Hz, 3H), 1.14 (s, 9H); MS (m/z): 458.24 (M+ H) ⁺ .

Example 64

6-chloro-2-fluoro- N- (4-(isopropylamino)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide

Using N ⁴ -isopropyl quinazolin-4,8-diamine (intermediate 57, 140 mg, 0.69 mmol), 6-chloro-2-fluoro-3-(pentamylaminomethyl)benzene Formic acid (intermediate 2, 223 mg, 0.78 mmol), ethylene dichloride (147 mg, 1.17 mmol), DMF (1 drop) and DIPEA (267 mg, 2.07 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared by the procedure described in Example 1 to give 40 mg of the title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.38 (s, 1H), 8.69 (d, J = 7.0 Hz, 1H), 8.48 (s, 1H), 8.16-8.14 (t, J = 5.8 Hz , 1H), 8.10-8.07 (m, 2H), 7.55-7.51 (t, J = 8.0 Hz, 1H), 7.42-7.40 (d, J = 8.4 Hz, 1H), 7.36-7.33 (t, J = 8.0 Hz, 1H), 4.56-4.51 (m, 1H), 4.31 (d, J = 5.8 Hz, 2H), 1.28 (s, 3H), 1.25 (s, 3H), 1.14 (s, 9H); MS (m /z): 472.40 (M ⁺ H) ⁺ .

Example 65

N- (4-(Tertiary butylamino)-2-methylquinazolin-8-yl)-6-chloro-2-fluoro-3-(pentamylaminomethyl)benzamide

Use N ⁴ -(t-butyl)-2-methylquinazoline-4,8-diamine (intermediate 58,100 mg, 0.43 mmol), 6-chloro-2-fluoro-3- (special) Pentamidine methyl)benzoic acid (intermediate 2,150 mg, 0.52 mmol), ethylene dichloride (82 mg, 0.65 mmol), DMF (1 drop) and DIPEA (166 mg, 1.29 mmol) of CH ₂ cl ₂ (3 mL), the title compound was prepared by following the procedures described in example 1 to give 46 mg of the title product. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.21 (s, 1H), 8.66 (d, J = 7.4 Hz, 1H), 8.15 (t, 1H), 8.10 (d, J = 8.0 Hz, 1H) ), 7.44 - 7.33 (m, 4H), 4.31 (d, J = 5.8 Hz, 2H), 2.48 (s, 3H), 1.14 (s, 9H); MS (m/z): 500.60 (M+H) ⁺ .

Example 66

2-fluoro-3 - ((3-hydroxy-2,2-dimethyl-propan-acyl amino) methyl) - N - (4- (3- ( trifluoromethyl) phenoxy) Quinazoline-8-yl)benzamide

Using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (intermediate 8,200 mg, 0.655 mmol), 6-chloro-2-fluoro-3-(3- Hydroxy-2,2-dimethylpropionamido)methyl)benzoic acid (intermediate 59, 237 mg, 0.78 mmol), ethylene dichloride (166 mg, 1.32 mmol), DMF (1 drop) and DIPEA (253 mg, 1.96 mmol) of _{CH 2 Cl 2 (3 mL)} , following the procedure described in example 1 the title compound was prepared to give 10 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.94 (s, 1H), 8.88 (d, 1H), 8.77 (s, 1H), 8.14 (m, 2H), 7.85 (m, 2H), 7.73 (s, 3H), 7.36 (m, 2H), 4.91 (t, 1H), 4.31 (d, 2H), 3.40 (m, 2H), 1.06 (s, 6H); MS [M+H] ⁺ : 591.29 .

Example 67

N- (4-(Tertiary butylamino)quinazolin-8-yl)-2-chloro-5-(pentamylaminomethyl)benzamide

Using N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 50 mg, 0.23 mmol), 2-chloro-5-(p-amylaminomethyl)benzoic acid (Intermediate 5, 93 mg, 0.34 mmol), sulphur chloride (1 mL) and EtOAc (EtOAc (EtOAc) Mg title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.11 (s, 1H), 8.69-8.67 (d, J = 7.4 Hz, 1H), 8.49 (s, 1H), 8.16-8.13 (m, 2H) , 7.58-7.38 (m, 5H), 4.31-4.29 (d, J = 5.6 Hz, 2H), 1.55 (s, 9H), 1.12 (s, 9H); MS (m/z): 468.42 (M+H) ) ⁺ .

Example 68

N- (4-(Tertiary butylamino)quinazolin-8-yl)-2,6-dimethyl-3-(pentamylaminomethyl)benzamide

Using N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 275 mg, 1.27 mmol), 2,6-dimethyl-3-(pentamylamine) Benzoic acid (intermediate 4,401 mg, 1.52 mmol), ethylene dichloride (230 mg, 1.82 mmol), DMF (1 drop) and DIPEA (392 mg, 3.04 mmol) in CH ₂ Cl ₂ (10 mL) The title compound was prepared following the procedure described in Example 1 to give 30 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.68 (s, 1H), 8.78-8.67 (d, J = 7.8 Hz, 1H), 8.44 (s, 1H), 8.13-8.10 (d, J = 8.4 Hz, 1H), 7.94 (t, 1H), 7.49-7.43 (m, 2H), 7.13-7.11 (m, 2H), 4.23 (d, 2H), 2.24 (s, 3H), 2.21 (s, 3H) ), 1.52 (s, 9H), 1.12 (s, 9H); MS [M+H] ⁺ : 462.44.

Example 69

N- (4-(Tertiary butylamino)quinazolin-8-yl)-6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido) A Benzomamide

Using N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-((3-hydroxy-2) ,2-dimethylpropionamido)methyl)benzoic acid (intermediate 59, 168 mg, 0.56 mmol), ethylene dichloride (116 mg, 0.92 mmol), DMF (1 drop) and DIPEA (178 mg) , 1.37 mmol) of _{CH 2 Cl 2 (2 mL)} , in 1 of the title compound was prepared following the procedure example to give 25 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.41 (s, 1H), 8.68 (d, J = 7.8 Hz, 1H), 8.51 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H) ), 8.11 (t, 1H), 7.52-7.38 (m, 4H), 4.91 (t, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.42 (d, 2H), 1.55 (s, 9H) , 1.08 (s, 6H); MS [M+H] ⁺ : 502.46.

Example 70

N- (4-(Tertiary butylamino)quinazolin-8-yl)-6-chloro-2-fluoro-3-(isobutylguanidinomethyl)benzamide

Use N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-(isobutylammonium Prepare the title according to the procedure described in Example 1, following the procedure described in Example 1, benzoic acid (intermediate 60, 188 mg, 0.69 mmol), sulfinium chloride (1 mL), and DIPEA (238 mg, 1.80 mmol) in THF (2 mL) Compound to give 13 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.42 (s, 1H), 8.69 (d, 1H), 8.50 (s, 1H), 8.37 (t, 1H), 8.15 (d, 1H), 7.52 - 7.40 (m, 4H), 4.32 (d, 2H), 1.55 (s, 9H), 1.03 (d, J = 6.3 Hz, 6H); MS[M+H] ⁺ : 474.34.

Example 71

N- (4-(Tertiary butylamino)quinazolin-8-yl)-2-chloro-4-fluoro-5-(pentamylaminomethyl)benzamide

Use N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 100 mg, 0.46 mmol), 2-chloro-4-fluoro-5-(pentamylamine) Benzoic acid (intermediate 63, 159 mg, 0.56 mmol), ethylene dichloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared following the procedure described in Example 1 to give 20 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.18 (s, 1H), 8.69-8.66 (d, J = 7.2 Hz, 1H), 8.4.7 (s, 1H), 8.16-8.11 (m, 2H), 7.62-7.57 (m, 2H), 7.52-7.45 (m, 2H), 4.31-4.29 (d, J = 5.7 Hz, 2H), 1.53 (s, 9H), 1.10 (s, 9H); [M+H] ⁺ : 486.45.

Example 72

N- (4-(Tertiary butylamino)quinazolin-8-yl)-2-chloro-4-fluoro-3-(pentamylaminomethyl)benzamide

Use N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 100 mg, 0.46 mmol), 2-chloro-4-fluoro-3-(pentamylamine) Benzoic acid (intermediate 64, 159 mg, 0.56 mmol), ethylene dichloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH ₂ Cl ₂ (5 mL) The title compound was prepared following the procedure described in Example 1 to afford 12 mg title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.05 (s, 1H), 8.71 - 8.69 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.15-8.13 (d, J = 7.8 Hz, 1H), 7.83 (t, 1H), 7.75-7.73 (m, 1H), 7.53-7.47 (m, 2H), 7.40-7.34 (t, J = 8.7 Hz, 1H), 4.43 (d, 2H) ), 1.54 (s, 9H), 1.08 (s, 9H); MS [M+H] ⁺ : 486.56.

Example 73

6-Chloro-2-fluoro-3- (isobutoxy acyl aminomethyl) - N - (4 - ( (2,2,2- trifluoroethyl) amino) quinazolin-8-yl) benzene Formamide

Using N ⁴ -(2,2,2-trifluoroethyl)quinazoline-4,8-diamine (intermediate 65, 70 mg, 0.29 mmol), 6-chloro-2-fluoro-3-( Isobutyrylmethyl)benzoic acid (intermediate 60, 118 mg, 0.43 mmol), sulfinium chloride (1 mL) and DIPEA (148 mg, 1.15 mmol) in THF (2 mL) The title compound was prepared to give 18 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.57 (s, 1H), 8.93 (t, 1H), 8.76-8.73 (d, J = 7.2 Hz, 1H), 8.61 (s, 1H), 8.38 (t, 1H), 8.12-8.09 (d, J = 9.3 Hz, 1H), 7.66-7.61 (t, J = 7.8 Hz, 1H), 7.40-7.38 (m, 2H), 4.47 (m, 2H), 4.32 (d, J = 4.8 Hz, 2H), 2.42 (m, 1H), 1.05-1.03 (d, J = 6.9 Hz, 6H); MS[M+H] ⁺ : 498.31.

Example 74

2- (difluoromethyl) -5- (aminomethyl isobutoxy XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) nicotinic XI amine

Use 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (intermediate 8,50 mg, 0.18 mmol), 2-(difluoromethyl)-5-(isobutyl)醯Aminomethyl)nicotinic acid (intermediate 66,56 mg, 0.18 mmol), ethylene dichloride (23 mg, 0.18 mmol), DMF (1 drop) and DIPEA (48 mg, 0.37 mmol) of CH ₂ cl ₂ (1.5 mL), the title compound was prepared by following the procedures described in example 1 to give 10 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.67 (s, 1H), 8.84 - 8.82 (d, J = 7.8 Hz, 1H), 8.79 (s, 1H), 8.71 (d, J = 1.8 Hz) , 1H), 8.48 (t, 1H), 8.21-8.19 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.89-7.86 (m, 2H), 7.76 (s, 3H), 7.42 7.06(t, J = 54.6 Hz, 1H), 4.44 - 4.42 (d, J = 5.4 Hz, 2H), 2.44 (m, 1H), 1.05 (d, J = 6.6 Hz, 6H); MS [M+H ] ⁺ : 560.45.

Example 75

N- (4-(Tertiary butylamino)quinazolin-8-yl)-2-(difluoromethyl)-5-(isobutylguanidinomethyl)nicotinamide

Use N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 100 mg, 0.46 mmol), 2-(difluoromethyl)-5-(isobutylamylamine Methyl)nicotinic acid (intermediate 66, 150 mg, 0.55 mmol), ethylene dichloride (104 mg, 0.83 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) of CH ₂ Cl ₂ ( The title compound was prepared following the procedure described in Example 1 to afford 12 mg title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 8.71 (s, 1H), 8.63 (m, 1H), 8.49 (m, 2H), 8.16 (d, 1H), 8. (m,1H), 7.46 (m, 2H), 7.22 (t, J = 54 Hz, 1H), 4.42 (d, 2H), 1.55 (s, 9H), 1.05 (d, J = 6.6 Hz, 6H) ;MS[M+H] ⁺ : 471.49.

Example 76

2- (difluoromethyl) -5- (aminomethyl isobutoxy XI) - N - (4- (isopropylamino) quinolin-8-yl) niacinamide

Using N ⁴ -isopropyl quinazolin-4,8-diamine (intermediate 57, 100 mg, 0.50 mmol), 2-(difluoromethyl)-5-(isobutylguanidinomethyl) Nicotinic acid (intermediate 66, 161 mg, 0.60 mmol), ethylene dichloride (113 mg, 0.90 mmol), DMF (1 drop) and DIPEA (192 mg, 1.49 mmol) of CH ₂ Cl ₂ (2 mL) The title compound was prepared following the procedure described in Example 1 to give 10 mg title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 8.71 (s, 1H), 8.64 (m, 1H), 8.48 (m, 2H), 8.08 (m, 3H), 7. (m,1H), 7.23 (t, J = 54 Hz, 1H), 4.44 (m, 1H), 4.41 (d, 2H), 2.50 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H) , 1.04 (d, J = 7.5 Hz, 6H); MS [M+H] ⁺ : 457.47.

Example 77

6-Chloro-2-fluoro-3- (isobutoxy acyl aminomethyl) - N - (4- (isopropylamino) quinolin-8-yl) benzoyl amine

Use N ⁴ -isopropyl quinazoline-4,8-diamine (intermediate 57, 50 mg, 0.25 mmol), 6-chloro-2-fluoro-3-(isobutylguanidinomethyl)benzene Formic acid (intermediate 60, 100 mg, 0.37 mmol), sulfinium chloride (1 mL) and EtOAc (EtOAc (EtOAc) 20 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.42 (s, 1H), 8.78-8.67 (d, J = 7.2 Hz, 1H), 8.48 (s, 1H), 8.37 (t, 1H), 8.11 -8.08 (d, J = 7.8 Hz, 2H), 7.53 (t, 1H), 7.41 (m, 2H), 4.55 (m, 1H), 4.31 (d, 2H), 2.50 (m, 1H), 1.27 ( d, J = 6.6 Hz, 6H), 1.05-1.03 (d, J = 6.9 Hz, 6H); MS [M+H] ⁺ : 458.47.

Example 78

2- (difluoromethyl) -5- (aminomethyl isobutoxy XI) - N - (4 - ( (2,2,2- trifluoroethyl) amino) quinazolin-8-yl) Nicotinamide

Using N ⁴ -(2,2,2-trifluoroethyl)quinazoline-4,8-diamine (intermediate 65, 48 mg, 0.20 mmol), 2-(difluoromethyl)-5- (Isobutylguanidinomethyl)nicotinic acid (intermediate 66, 107 mg, 0.40 mmol), ethylene dichloride (50 mg, 0.40 mmol), DMF (1 drop) and DIPEA (127 mg, 0.99 mmol) the _{CH 2 Cl 2 (2 mL)} , following the procedure of example 1 the title compound was prepared to give 5 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.40 (s, 1H), 8.95 (t, 1H), 8.71 (d, 1H), 8.61 (s, 1H), 8.48 (t, 1H), 8.07 (m, 2H), 7.65 (t, 1H), 7.41 - 7.05 (t, J = 54.0 Hz, 1H), 4.42 (m, 4H), 2.50 (m, 1H), 1.05 (d, J = 7.2 Hz, 6H); MS [M+H] ⁺ : 495.52.

Example 79

N- (4-(Tertiary butylamino)quinazolin-8-yl)-6-chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropanamido) A Benzomamide

Using N ⁴ -(t-butyl)quinazoline-4,8-diamine (intermediate 55, 50 mg, 0.23 mmol), 6-chloro-2-fluoro-3-((3-fluoro-2) ,2-dimethylpropionamido)methyl)benzoic acid (intermediate 67,84 mg, 0.27 mmol), ethylene dichloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (89 mg , 0.69 mmol) of _{CH 2 Cl 2 (2 mL)} , in 1 of the title compound was prepared following the procedure example to give 30 mg of the title product. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.41 (s, 1H), 8.69-8.66 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 8.33 (t, 1H), 8.18 -8.15 (d, J = 9.3 Hz, 1H), 7.54-7.34 (m, 4H), 4.48-4.33 (m, 4H), 1.55 (s, 9H), 1.16 (s, 6H); MS (m/z ): 504.64 (M+H) ⁺ .

Example 80

2- (difluoromethyl) - N - (4- (4- fluoro-3- (trifluoromethyl) phenoxy) quinolin-8-yl) -5- (aminomethyl isobutoxy XI) Nicotinamide

Using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinoline-8-amine (Intermediate 44, 50 mg, 0.16 mmol), 2-(difluoromethyl)-5- (Isobutylguanidinomethyl)nicotinic acid (intermediate 66, 52 mg, 0.19 mmol), ethylene dichloride (37 mg, 0.29 mmol), DMF (1 drop) and DIPEA (74 mg, 0.57 mmol) the _{CH 2 Cl 2 (2 mL)} , following the procedure of example 1 the title compound was prepared to give 7 mg of the title product. ¹ H NMR (300 MHz, CDCl ₃ ): δ 10.39 (s, 1H), 8.93 (d, 1H), 8.75 (s, 1H), 8.60 (d, 1H), 8.07 (m, 2H), 7.66 (t) , 1H), 7.47 (m, 1H), 7.37-7.15 (m, 2H), 6.60 (d, J = 5.4 Hz, 1H), 4.63-4.60 (d, J = 6.9 Hz, 2H), 2.45 (m, 1H), 1.21 (d, J = 6.9 Hz, 6H); MS (m/z): 577.97 (M+H) ⁺ .

Pharmacological activity

In vitro protocol for screening mPGES-1 inhibitors:

mPGES-1 (microsomal prostaglandin E synthetase-1) is a microsomal enzyme that is endogenously accommodating PGH by isomerization in the presence of reduced glutathione (GSH). ₂ (Prostaglandin H ₂ ) is converted to the product PGE ₂ (prostaglandin E ₂ ). The mPGES-1 inhibitor was screened by using an anti-PGE ₂ antibody-based detection method to evaluate the ability of the mPGES-1 inhibitor to inhibit the formation of PGE ₂ from PGH _{2 in the} presence of mPGES-1. Recombinant human mPGES-1 is produced internally by expression in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489-495). The analysis was established at a protein concentration of 40-60 μg/mL using the coarse microsome fraction. Test compounds were prepared in 100% dimethyl hydrazine (DMSO) to obtain a 20 mM stock solution and then diluted using assay buffer containing 0.1 M potassium phosphate buffer and 2 mM EDTA. The final concentration of DMSO in the reaction was 0.5% (v/v). The negative control contained all analytical reagents except the enzyme. The positive control contained the enzyme reactant in the absence of any inhibitor. Test compounds were incubated in assay buffer containing 2.5 mM GSH and mPGES-1 enzyme for 10 minutes, followed by addition of PGH ₂ at a concentration of 15 μM for 1 minute. The reaction was stopped by the addition of stannous chloride (11 mg/ml) and the PGE ₂ content was measured by the HTRF kit (CisBio) (Masse F et al. (2005), Journal of Biomolecular Screening 10 (6) 599-605. ; Goedken RE et al. (2008), Journal of Biomolecular Screening 13 (7): 619-625).

The inhibition of mPGES-1 enzyme activity was measured using the percentage of reactions occurring in the positive control. The concentration response curve is plotted using the percent inhibition of the maximum enzymatic reaction. By using GraphPad PRISM software nonlinear regression analysis IC ₅₀ value is calculated from the concentration-response curve.

The prepared compounds were tested using the above analytical procedure and the results obtained are given in Table 1. Selected instance is given percent inhibition at 1.0 μM concentration of 10.0 μM and as well as the IC ₅₀ (nM) in the table before. Test compounds were prepared using the above procedure and found to analyze an IC ₅₀ less than 200 nM, preferably less than 100 nM, more preferably less than 50 nM, or most preferably less than 20 nM.

The IC ₅₀ (nM) values for the compounds are set forth in Table 1, where "A" means an IC ₅₀ value of less than 50 nM, "B" means an IC ₅₀ value in the range of 50.01 to 100.0 nM and "C" means an IC ₅₀ value. More than 100 nM.

Screening for mPGES-1 inhibitors using A549 cell-based assays

Inhibition of mPGES-1 enzyme in A549 cell lines was monitored for inhibition of IL-1β-induced PGE ₂ release. A549 cells were maintained in DMEM medium containing 10% FBS and 1% penicillin-streptomycin solution in 5% CO ₂ at 37 °C. Cells were seeded in 96-well plates in DMEM containing 1% penicillin-streptomycin and 2% FBS 24 hours prior to analysis to obtain approximately 40,000 cells per well on the day of the experiment. The analysis was performed in a total volume of 200 μL. The test compound was dissolved in dimethyl hydrazine (DMSO) to prepare a 2 mM stock solution and then diluted using normal DMEM. The final concentration of DMSO in the reaction was 0.55% (v/v). Cells were treated with test compounds for 30 minutes, followed by addition of IL-1β at a final concentration of 10 ng/mL for 16-20 hours. The plates were then centrifuged at 1000 rpm for 10 minutes at 4 °C. And the supernatant was collected by adding a PGE CisBio HTRF kit supplied to the conjugate and anti-PGE ₂ -D2 ₂ cryptate analyzed in 96-well half-area Blackwell EIA / RIA plate. The assay plates were incubated overnight at 4-5 °C, then read in an Artemis (K-101) (Japan) HTRF disk reader and the PGE ₂ content was calculated by extrapolation from the standard curve.

The concentration response curve is plotted as the % of the maximum response obtained in the absence of the test antagonist. By using GraphPad PRISM software nonlinear regression analysis IC ₅₀ value is calculated from the concentration-response curve.

Claims (40)

A compound of formula (II): Or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^c ; Z ¹ and Z ³ which may be the same or different are independently selected from N and CR ² ; G ¹ is selected from N and CR ³ ; The restriction condition is that at least one of Z ¹ , Z ³ and G ¹ is N; Q ¹ , Q ² , Q ³ and Q ⁴ which may be the same or different are independently selected from N, CH and CR ⁴ ; the limitation condition is Q ² , Q ³ and Q ^{4 are} not N at the same time; W is selected from substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl , substituted or unsubstituted halogen C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, and substituted or unsubstituted Substituted tetrahydrofuranyl; R ¹ is selected from substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or not Substituted halogen C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _{6 -14} aryl, substituted or unsubstituted 3-15 membered heterocyclic group and substituted or unsubstituted 5-14 membered heteroaryl; same Or different R ² and R ³ are each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted a C _1-8 alkoxy group, a substituted or unsubstituted halogen C _1-8 alkyl group, a substituted or unsubstituted hydroxy C _1-8 alkyl group, a substituted or unsubstituted C _3-12 a cycloalkyl group and a substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl group; at each occurrence, R ^{4 is} independently selected from the group consisting of halogen, nitro, cyano, hydroxy, substituted Or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted Or unsubstituted halogen C _1-8 alkyl, substituted or unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, and substituted or unsubstituted C _3-8 cycloalkyl C _1-8 alkyl; at each occurrence, R ^{c is} independently selected from substituted or unsubstituted C _1-8 alkyl and substituted or unsubstituted C _{6 -14} aryl C _1-8 alkyl; or R ^c and R ¹ together with the N to which they are attached form a morpholine ring; may be the same or different R ^x and R ^y are each independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, and substituted or unsubstituted C _6-14 aryl C _1-8 alkyl; And "n" is an integer ranging from 1 to 4, including both 1 and 4. A compound of claim 1, wherein Y is O or NH. A compound of claim 1, wherein Z ¹ is N, Z ³ is CH and G ¹ is CH. A compound of claim 1, wherein Z ¹ , Z ³ are N and G ¹ is CH. A compound of claim 1, wherein Z ¹ is CH, Z ³ is N and G ¹ is CH. A compound according to claim 1 wherein R ² is hydrogen, methyl or trifluoromethyl. A compound of claim 1, wherein R ³ is hydrogen or methyl. A compound according to claim 1, wherein Q ¹ is N, CH or CR ⁴ , Q ² is CH or CR ⁴ , Q ³ is N or CH, and Q ⁴ is CR ⁴ . The compound of claim 1, wherein R ⁴ is OCH ₃ , CH ₃ , CHF ₂ , Cl or F. The compound of claim 1, wherein R ^x and R ^y are hydrogen. For example, the compound of claim 1 of the patent scope, wherein "n" is 1. The compound of claim 1, wherein R ¹ is methyl, ethyl, isopropyl, tert-butyl, 2,2,2-trifluoroethyl, 3-(trifluoromethyl)phenyl , 4-(Trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-4-(three Fluoromethyl)phenyl, 6-(trifluoromethyl)pyridin-3-yl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl (1 s , 4 s ) -4-(trifluoromethyl)cyclohexyl or (1 r , 4 r )-4-(trifluoromethyl)cyclohexyl. The compound of claim 1, wherein W is isopropyl, tert-butyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, Tetrahydrofuranyl or ( S )-tetrahydrofuran-2-yl. A compound of formula (III): Or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of NH and O; and Z ¹ and Z ³ which may be the same or different are independently selected from N and CR ² ; the limitation is at least one of Z ¹ and Z ³ Is N; the same or different Q ¹ , Q ² , Q ³ and Q ^{4 are} independently selected from N, CH and CR ⁴ ; the limitation is that Q ² , Q ³ and Q ^{4 are} not N at the same time; W system a substituted or unsubstituted C _1-8 alkyl group, a substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl group, a substituted or unsubstituted halogen C _1-8 alkane a substituted or unsubstituted hydroxy C _1-8 alkyl group, a substituted or unsubstituted C _3-12 cycloalkyl group, and a substituted or unsubstituted tetrahydrofuranyl group; R ¹ is selected from substituted or Unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy C _1-8 alkyl, substituted or unsubstituted halogen C _1-8 alkyl, substituted or Unsubstituted hydroxy C _1-8 alkyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _6-14 aryl, substituted or unsubstituted 3- 15 membered heterocyclic group and substituted or unsubstituted 5-14 membered heteroaryl; the same or different R ² and R ^{3 are present} at each time Currently all independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy, and substituted or unsubstituted halide C _1-8 alkyl; and at each occurrence, R ^{4 is} independently selected from halo, nitro, cyano, hydroxy, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted a C _1-8 alkoxy group, a substituted or unsubstituted halogen C _1-8 alkyl group, and a substituted or unsubstituted C _3-12 cycloalkyl group. A compound according to claim 14 wherein Z ¹ is N and Z ³ is CH or N. A compound according to claim 14 wherein Z ¹ is CH and Z ³ is N. A compound according to claim 14 wherein R ² is hydrogen, methyl or trifluoromethyl. A compound according to claim 14 wherein R ³ is hydrogen or methyl. A compound according to claim 14 wherein Q ¹ is N, CH or CR ⁴ , Q ² is CH or CR ⁴ , Q ³ is N or CH, and Q ⁴ is CR ⁴ . A compound according to claim 14 wherein R ⁴ is OCH ₃ , CH ₃ , CHF ₂ , Cl or F. A compound according to claim 14 wherein R ¹ is methyl, ethyl, isopropyl, tert-butyl, 2,2,2-trifluoroethyl, 3-(trifluoromethyl)phenyl , 4-(Trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-4-(three Fluoromethyl)phenyl, 6-(trifluoromethyl)pyridin-3-yl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl (1 s , 4 s ) -4-(trifluoromethyl)cyclohexyl or (1 r , 4 r )-4-(trifluoromethyl)cyclohexyl. A compound according to claim 14 wherein W is isopropyl, tert-butyl, 1-fluoro-2-methylpropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, Tetrahydrofuranyl or ( S )-tetrahydrofuran-2-yl. A compound selected from 2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amino) isoquinoline 5-yl) benzoyl amine; 3-chloro-6- (aminomethyl pivaloyl XI) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amino) isoquinoline 5-yl) pyridine A Amides; 2,6-dimethyl-3- (pivaloyl acyl aminomethyl) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amine ) isoquinolin-5-yl) benzoyl amine; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (1 - ( (3- ( trifluoromethyl) phenyl) amine ) isoquinolin-5-yl) benzoyl amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (1- (3- ( trifluoromethyl) phenoxy yl) isoquinolin-5-yl) benzoyl amine; 3-chloro-6- (aminomethyl pivaloyl XI) - N - (1- (3- ( trifluoromethyl) phenoxy) iso quinolin-5-yl) pyridine A Amides; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (1- (3- ( trifluoromethyl) phenoxy) isoquinoline - 5- yl) benzoyl amine; 3-chloro-6- (aminomethyl pivaloyl XI) - N - (4 - ( (3- ( trifluoromethyl) phenyl) amino) quinazolin - 8- yl) pyridine A Amides; 3-chloro-6- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl ) picolinate Amides; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (4- (3- (Trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4- (3 - (trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4- ( (3- (trifluoromethyl) phenyl) amino) quinazolin-8-yl) benzoyl amine; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (4- ( (3-(Trifluoromethyl)phenyl)amino)quinazolin-8-yl)benzamide; 2-chloro- N- (4-((4,4-difluorocyclohexyl))amine Quinazoline-8-yl)-5-(pentamylaminomethyl)benzamide; 2-chloro- N- (4-((4,4-dimethylcyclohexyl)oxy)) quinazolin-8-yl) -5- (aminomethyl pivaloyl XI) benzoyl amine; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine; 3-chloro-6- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl ) phenoxy) quinolin-8-yl) pyridine carboxylic acyl amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4- (3- ( trifluoromethyl ) phenoxy) quinolin-8-yl) benzoyl amine; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (8 - ( (3- ( trifluoromethyl) phenyl Amino)quinolin-4-yl)benzamide;6-chloro- N- (4-((4,4-difluorocyclohexyl))amine Quinazoline-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide; 6-chloro-2-fluoro- N- (4-((2-fluoro-5) -(Trifluoromethyl)phenyl)amino)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide; 6-chloro- N- (4-((4) , 4-methylcyclohexyl) amino) quinazolin-8-yl) -2-fluoro-3- (pivaloyl acyl aminomethyl) benzoyl-amine; (S) - N - ( 4- Chloro-2-fluoro-3-((4-((3-(trifluoromethyl)phenyl)amino)) quinazolin-8-yl)amine,carboxamido)benzyl)tetrahydrofuran-2-methyl Indoleamine; 6-chloro- N- (4-((4,4-dimethylcyclohexyl)oxy)quinazolin-8-yl)-2-fluoro-3-(p-amylaminomethyl) Benzoguanamine; 6-chloro-2-fluoro- N- (4-((4-fluoro-3-(trifluoromethyl)phenyl))amino)quinazoline-8-yl)-3- (pivalate acyl aminomethyl) benzoyl-amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( ((1 s, 4 s) -4 - (trifluoromethyl) cyclohexyl) oxy) quinazolin-8-yl) benzoyl amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 -(((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)oxy)quinazolin-8-yl)benzamide; 6-chloro-2-fluoro- N- (4 -(2-fluoro-5-(trifluoromethyl)phenoxy)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide; 6-chloro-2- - N - (4 - (( 2- fluoro-4- (trifluoromethyl) phenyl) amino) quinazolin-8-yl) -3- (aminomethyl pivaloyl XI) benzoyl amine ; chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( (6- ( trifluoromethyl) pyridin-3-yl) amino) quinazolin -8 - yl) benzoyl amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( (3- ( trifluoromethyl) phenyl) amino) quinolin Phenyl-8-yl)benzamide; 6-chloro- N- (4-((4,4-dimethylcyclohexyl)amino)-2-(trifluoromethyl)quinazoline-8- 2-fluoro-3-(pentamylaminomethyl)benzamide; 6-chloro-2-fluoro- N- (2-methyl-4-((3-(trifluoromethyl)) Phenyl)amino)quinazoline-8-yl)-3-(pentamylaminomethyl)benzamide; 6-chloro- N- (1-((4,4-dimethyl) Cyclohexyl)oxy)isoquinolin-5-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide; 6-chloro-2-fluoro-3-(pivalamylamine) Methyl) -N- (1-((( 1r , 4r )-4-(trifluoromethyl)cyclohexyl)amino)isoquinolin-5-yl)benzamide; 6-chloro 2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) amino) quinazolin - 8- yl) benzoyl amine; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (1 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl ) Yloxy) isoquinolin-5-yl) benzoyl amine; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (4 - ( ((1 r, 4 r) -4- ( Trifluoromethyl)cyclohexyl)oxy)quinazolin-8-yl)benzamide; 6-chloro-2-fluoro- N- (4-(2-fluoro-5-(trifluoromethyl)) Phenoxy)quinoline-8-yl)-3-(pentamylaminomethyl)benzamide; 2-chloro- N- (1-(2-fluoro-5-(trifluoromethyl)) Phenoxy)isoquinolin-5-yl)-5-(pentamylaminomethyl)benzamide; 6-chloro-2-fluoro- N- (7-methyl-4-((3) -(trifluoromethyl)phenyl)amino)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide; 6-chloro- N- (4-ethoxyl) Quinazoline-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide; 2-chloro- N- (1-((2-fluoro-4-(trifluoromethyl)) Phenyl)amino)isoquinolin-5-yl)-5-(pentamylaminomethyl)benzamide; 2-chloro-5-(pentamylaminomethyl) -N -(1-((4-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)benzamide; 2-chloro-5-(p-amylaminomethyl) -N - (1- (4- (trifluoromethyl) phenoxy) isoquinolin-5-yl) benzoyl amine; 2-chloro-5- (aminomethyl pivaloyl XI) - N - (1 -(((1 s , 4 s )-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-5-yl)benzamide; 2-chloro- N -(1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-yl)-5-(pentamylaminomethyl)benzamide; 6-chloro- 2-methoxy-3- (aminomethyl pivaloyl XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinolin-8-yl) benzoyl amine; 6 - chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (1 - ( ((1 r, 4 r) -4- ( trifluoromethyl) cyclohexyl) oxy) isoquinoline 5-oxo-2-fluoro- N- (4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinolin-8-yl)-3 -(p-amylaminomethyl)benzamide;6-chloro-2-fluoro- N- (4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazoline-8 - yl) -3- (aminomethyl pivaloyl XI) benzoyl amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (4- (4- ( three Fluoromethyl)phenoxy)quinolin-8-yl)benzamide; 6-chloro- N- (4-((4,4-dimethylcyclohexyl)amino)-2-methylquin Oxazolin-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide; 6-chloro-2-fluoro- N- (2-methyl-4-(3-( Trifluoromethyl)phenoxy)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide; 6-chloro-2-fluoro- N- (4-(isopropylamine) 2-methylquinazolin-8-yl)-3-(pentamylaminomethyl)benzamide; 6-chloro-2-fluoro- N- (2-methyl-4- (N -morpholinyl)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide;6-chloro-2-fluoro- N- (4-isopropoxyquinazoline -8-yl)-3-(pentamylaminomethyl)benzamide; 6-chloro- N- (4-((4,4-difluorocyclohexyl)amino)-2-methyl Quinazoline-8-yl)-2-fluoro-3-(pentamylaminomethyl)benzamide; 6-chloro- N- (4-(dimethylamino)quinazoline-8- 2-fluoro-3-(pentamylaminomethyl)benzamide; N- (4-(t-butylamino)quinazolin-8-yl)-6-chloro-2- Fluoro-3-(pentamylaminomethyl)benzamide; 6-chloro- N- (4-ethoxyquinolin-8-yl)-2-fluoro-3-(pentamylamine) Methyl)benzamide;6-chloro-2-fluoro- N- (4-(isopropylamino)quinazolin-8-yl)-3-(pentamylaminomethyl)benzamide N- (4-(Tertiary butylamino)-2-methylquinazolin-8-yl)-6-chloro-2-fluoro-3-(pentamylaminomethyl)benzamide ; 2-fluoro-3 - ((3-hydroxy-2,2-dimethyl-propan-acyl amino) methyl) - N - (4- (3- ( trifluoromethyl) phenoxy Quinazoline-8-yl)benzamide; N- (4-(T-butylamino)quinazolin-8-yl)-2-chloro-5-(pentamylaminomethyl) benzoyl amine; N - (4- (tertiary butylamino) quinazolin-8-yl) -2,6-dimethyl-3- (Laid Acyl aminomethyl) benzoyl-amine; N - (4- (tertiary butylamino) quinazolin-8-yl) -6-chloro-2-fluoro-3 - ((3-hydroxy-2, 2-dimethylpropionamido)methyl)benzamide; N- (4-(t-butylamino)quinazolin-8-yl)-6-chloro-2-fluoro-3-( Isobutylguanidinomethyl)benzamide; N- (4-(t-butylamino)quinazolin-8-yl)-2-chloro-4-fluoro-5-(pentamylamine Methyl)benzamide; N- (4-(T-butylamino)quinazolin-8-yl)-2-chloro-4-fluoro-3-(pentamylamino)benzamide Amides; 6-chloro-2-fluoro-3- (isobutoxy acyl aminomethyl) - N - (4 - ( (2,2,2- trifluoroethyl) amino) quinazoline-8 yl) benzoyl amine; 2- (difluoromethyl) -5- (aminomethyl isobutoxy XI) - N - (4- (3- ( trifluoromethyl) phenoxy) quinazoline - 8-yl)nicotinamide; N- (4-(t-butylamino)quinazolin-8-yl)-2-(difluoromethyl)-5-(isobutylguanidinomethyl) niacinamide; 2- (difluoromethyl) -5- (aminomethyl isobutoxy XI) - N - (4- (isopropylamino) quinolin-8-yl) niacinamide; 6 - chloro-2-fluoro-3- (isobutoxy acyl aminomethyl) - N - (4- (isopropylamino) quinolin-8-yl) benzoyl amine; 2- (difluoromethyl) 5- (isobutyl-methyl-amino acyl) - N - (4 - ( (2,2,2- trifluoroethyl) amino) Quinazoline-8-yl)nicotinium amide; N- (4-(t-butylamino)quinazolin-8-yl)-6-chloro-2-fluoro-3-((3-fluoro-) 2,2-dimethyl-propan-acyl amino) methyl) benzoyl-amine; 2- (difluoromethyl) - N - (4- (4- fluoro-3- (trifluoromethyl) phenoxy a quinoline-8-yl)-5-(isobutylguanidinomethyl)nicotinamide; and a pharmaceutically acceptable salt thereof. a compound of the formula: Or a pharmaceutically acceptable salt thereof. a compound of the formula: Or a pharmaceutically acceptable salt thereof. a compound of the formula: Or a pharmaceutically acceptable salt thereof. a compound of the formula: Or a pharmaceutically acceptable salt thereof. a compound selected from the group consisting of 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine; N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4, 8-diamine; 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinoline-8-amine; 2-methyl- N ⁴ -(3-(trifluoromethyl)phenyl a quinazoline-4,8-diamine; and a pharmaceutically acceptable salt thereof. a compound selected from the group consisting of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinazoline; 8-nitro- N- (3-(trifluoromethyl)phenyl)quina Oxazolin-4-amine; 4-(4-fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinoline; 2-methyl-8-nitro- N- (3-( Trifluoromethyl)phenyl)quinazolin-4-amine; and pharmaceutically acceptable salts thereof. a compound selected from the group consisting of 2-chloro-6-fluoro- N- (4-((2-fluoro-5-(trifluoromethyl)phenyl)amino) quinazolin-8-yl)benzimidazole amine; 6-chloro-2-fluoro-3- (pivaloyl acyl aminomethyl) - N - (quinolin-8-yl) benzoyl amine; 4-chloro-2-fluoro-3 - ((4 -((3-(Trifluoromethyl)phenyl)amino)quinazolin-8-yl)amine,carboxyamino)benzylidenecarboxylic acid, tert-butyl ester; N ¹ -(3-(trifluoro Methyl)phenyl)isoquinoline-1,5-diamine; 5-nitro- N- (3-(trifluoromethyl)phenyl)isoquinolin-1-amine; 1-(3-( Trifluoromethyl)phenoxy)isoquinolin-5-amine; 5-nitro-1-(3-(trifluoromethyl)phenoxy)isoquinoline; N ⁴ -(3-(trifluoro) Methyl)phenyl)quinazoline-4,8-diamine; 8-nitro- N- (3-(trifluoromethyl)phenyl)quinazolin-4-amine; 4-(3-( Trifluoromethyl)phenoxy)quinazoline-8-amine; 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinazoline; N ⁴ -(4,4-di Fluorocyclohexyl)quinazoline-4,8-diamine; N- (4,4-difluorocyclohexyl)-8-nitroquinazolin-4-amine; 4-((4,4-dimethyl) Cyclohexyl)oxy)quinazoline-8-amine; 4-((4,4-dimethylcyclohexyl)oxy)-8-nitroquinazoline; 4-(3-(trifluoromethyl) Phenoxy)quinoline-8-amine; 8-nitro-4-(3-(trifluoromethyl)phenoxy ) Quinoline; N ⁸ - (3- (trifluoromethyl) phenyl) quinoline-4,8-diamine; N ⁴ - (4- methoxybenzyl) - N ⁸ - (3- ( Trifluoromethyl)phenyl)quinoline-4,8-diamine; N ⁴ -(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine; N - (2-fluoro-5-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine; N ⁴ -(4,4-dimethylcyclohexyl)quinazoline-4,8 -diamine; N- (4,4-dimethylcyclohexyl)-8-nitroquinazolin-4-amine; N ⁴ -(4-fluoro-3-(trifluoromethyl)phenyl)quina Oxazoline-4,8-diamine; N- (4-fluoro-3-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine; 8-nitro-4-(( (1 s , 4 s ) -4-(trifluoromethyl)cyclohexyl)oxy)quinazoline; 8-nitro-4-(((1 r ,4 r )-4-(trifluoromethyl) Cyclohexyl)oxy)quinazoline; 4-(((1 s , 4 s )-4-(trifluoromethyl)cyclohexyl)oxy)quinazoline-8-amine; 4-((( 1 r , 4 r ) -4-(trifluoromethyl)cyclohexyl)oxy)quinazoline-8-amine; 4-(2-fluoro-5-(trifluoromethyl)phenoxy) quinazoline -8-8-amine; 4-(2-fluoro-5-(trifluoromethyl)phenoxy)-8-nitroquinazoline; N ⁴ -(2-fluoro-4-(trifluoromethyl) Phenyl)quinazoline-4,8-diamine; N- (2-fluoro-4-(trifluoromethyl)phenyl)-8-nitroquinazolin-4-amine; N ⁴ -(6 - (trifluoromethyl)pyridin-3-yl)quinazoline-4,8-diamine; 8-nitro- N- (6-(trifluoromethyl)pyridin-3-yl)quinazoline-4 -amine; N ⁴ -(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine; 8-nitro- N- (3-(trifluoromethyl)phenyl)quinoline- 4-amine; N ⁴ -(4,4-dimethylcyclohexyl)-2-(trifluoromethyl)quinazoline-4,8-diamine; N -(4,4-dimethylcyclohexyl )-8-nitro-2-(trifluoromethyl)quinazolin-4-amine; 2-methyl- N ⁴ -(3-(trifluoromethyl)phenyl)quinazoline-4,8 -diamine; 2-methyl-8-nitro- N- (3-(trifluoromethyl)phenyl)quinazolin-4-amine; 1-((4,4-dimethylcyclohexyl) Oxy)isoquinoline-5-amine; 1-((4,4-dimethylcyclohexyl)oxy)-5-nitroisoquinoline; N ¹ -((1 r ,4 r )-4 -(trifluoromethyl)cyclohexyl)isoquinoline-1,5-diamine; 5-nitro- N -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)isoquine啉-1-amine; N ⁴ -((1 r ,4 r )-4-(trifluoromethyl)cyclohexyl)quinazoline-4,8-diamine; 8-nitro- N -((1 r , 4 r ) -4-(trifluoromethyl)cyclohexyl)quinazolin-4-amine; 5-nitro-1-((1 r ,4 r )-4-(trifluoromethyl) cyclohexyl) oxy) isoquinoline; 5-nitro -1 - (((1 s, 4 s) -4- ( trifluoromethyl) cyclohexyl) oxy) isoquinoline ; 1 - (((1 r , 4 r) -4- ( trifluoromethyl) cyclohexyl) oxy) isoquinolin-5-amine; 1 - (((1 s , 4 s) -4- ( Trifluoromethyl)cyclohexyloxy)isoquinolin-5-amine; 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinoline-8-amine; 4-(2- Fluoro-5-(trifluoromethyl)phenoxy)-8-nitroquinoline; 1-(2-fluoro-5-(trifluoromethyl)phenoxy)isoquinolin-5-amine; -(2-fluoro-5-(trifluoromethyl)phenoxy)-5-nitroisoquinoline; 4-ethoxyquinazolin-8-amine; 4-ethoxy-8-nitro Quinazoline; N ¹ -(2-fluoro-4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine; N- (2-fluoro-4-(trifluoromethyl)benzene 5-)-nitroisoquinolin-1-amine; N ¹ -(4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine; 5-nitro- N- (4 -(trifluoromethyl)phenyl)isoquinolin-1-amine; 1-(4-(trifluoromethyl)phenoxy)isoquinolin-5-amine; 5-nitro-1-(4 -(trifluoromethyl)phenoxy)isoquinoline; 1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-amine; 1-(4-fluoro-3 -(trifluoromethyl)phenoxy)-5-nitroisoquinoline; 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinoline-8-amine; 4-(4 -fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinoline; 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazoline-8-amine 4-(4-fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinazoline; 4-(4-(trifluoromethyl)phenoxy)quinoline-8-amine; 8-nitro-4-(4-(trifluoromethyl)phenoxy)quinoline; N ⁴ -(4,4-dimethylcyclohexyl)-2-methylquinazoline-4,8- Diamine; N- (4,4-dimethylcyclohexyl)-2-methyl-8-nitroquinazolin-4-amine; 2-methyl-4-(3-(trifluoromethyl) Phenoxy)quinazoline-8-amine; 2-methyl-8-nitro-4-(3-(trifluoromethyl)phenoxy)quinazoline; N ⁴ -isopropyl-2- Methyl quinazoline-4,8-diamine; N -isopropyl-2-methyl-8-nitroquinazolin-4-amine; 2-methyl-4-(N-morpholinyl) Quinazoline-8-amine; 4-(2-methyl-8-nitroquinazolin-4-yl)morpholine; 4-isopropoxyquinazoline-8-amine; 4-isopropoxy -8-nitroquinazoline; N ⁴ -(4,4-difluorocyclohexyl)-2-methylquinazoline-4,8-diamine; N -(4,4-difluorocyclohexyl -2-methyl-8-nitroquinazolin-4-amine; N ⁴ -(t-butyl)quinazoline-4,8-diamine; N- (t-butyl)-8- Nitroquinazolin-4-amine; N ⁴ -isopropylquinazoline-4,8-diamine; N -isopropyl-8-nitroquinazolin-4-amine; N ⁴ - Tributyl)-2-methylquinazoline-4,8-diamine; N- (t-butyl)-2- Methyl-8-nitroquinazolin-4-amine; N ⁴ -(2,2,2-trifluoroethyl)quinazoline-4,8-diamine; 8-nitro- N- (2 , 2,2-trifluoroethyl)quinazolin-4-amine; 3-chloro-6-(pentamylaminomethyl)pyridinecarboxylic acid; 2,6-dimethyl-3-(pentylene Aminomethyl)benzoic acid; 6-chloro-2-methoxy-3-(pentamylaminomethyl)benzoic acid; and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 31, wherein the pharmaceutically acceptable excipient is a carrier or a diluent. A method of treating a mPGES-1 mediated disease, disorder or syndrome in an individual comprising administering an effective amount of a compound as in claim 1 of the patent application. A method of treating a disease, disorder, syndrome or condition selected from the group consisting of inflammation, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritability Intestinal syndrome, pain, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, lower back pain, fibromyalgia, myofascial disorders, viral infections, influenza, common cold, herpes zoster, Hepatitis C, AIDS, bacterial infection, fungal infection, dysmenorrhea, burns, surgery or dental procedures, malignant tumors, high prostaglandin E syndrome, classic Bartter syndrome, synovitis, atherosclerosis, gout, Arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, rheumatic fever, joint adhesion spondylitis, Hodgkin's Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes, cancer , neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis), autoimmune diseases, allergic conditions, rhinitis , ulcer, mild to moderate active ulcerative colitis, familial adenoma polyp, coronary heart disease, and sarcoma-like disease, the method comprising administering a compound as in claim 1 of the patent application. The method of claim 34, wherein the disease, condition, syndrome or condition is pain. The method of claim 34, wherein the disease, condition, syndrome or condition is chronic or acute pain. The method of claim 34, wherein the disease, condition, syndrome or condition is rheumatoid arthritis pain or osteoarthritis pain. The method of claim 34, wherein the disease, condition, syndrome or condition is inflamed. The method of claim 34, wherein the disease, condition, syndrome or condition is a neurodegenerative disorder selected from the group consisting of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. A method of treating, preventing or managing cancer comprising administering to an individual in need of such treatment an effective amount of a compound as in claim 1 of the scope of the patent application.