TW201111360A - Novel compounds - Google Patents

Abstract

The present disclosure relates to compounds of formula (I): which are inhibitors of p38 mitogen-activated protein kinase enzymes, particularly the alpha and gamma kinase sub-types thereof, and their use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, such as COPD.

Description

201111360 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a compound which is p38 via mitp- gen (activated protein kinase enzyme, particularly for its inhibitors of 丫 kinase subtype ( Represented herein as a p38 map kinase inhibitor, and equivalent to therapeutic use, including in pharmaceutical compositions, particularly in the treatment of inflammatory diseases, including inflammatory diseases of the lung, such as c〇pD. [Prior Art] The p38 MAPK isoforms (is〇f〇rm) have been confirmed (α ' β ' γ and δ , respectively), each of which exhibits a tissue-specific expression pattern. ρ38 ΜΑΡΚα and β isoforms are generally expressed throughout the body. And found in many different cell types. The p38 ΜΑΡΚα & ρ isomers are inhibited by specific known small molecule ρ3 8 ΜΑρκ inhibitors. The patterns of earlier compounds are generally expressed due to these heterogeneous weights. And the compound is highly toxic due to the deviation-target (〇ff_target) effect. More recent inhibitors have demonstrated selectivity and overall selectivity for P38 MAPKcx and beta isoforms. Wide safety. 〃 ^ ρ38 ΜΑΡΚ γ and δ isomers are not known as a whole. These isoforms are expressed on specific tissues/cells (not like ρ38 α and ρ38 ρ isomers). ρ38 ΜΑΡΚ-δ The overall weight of the structure is expressed in the gland, the sputum, the lungs, the small intestine and the kidney. It is also abundant in macrophages (Smith, SJ (2006) British Journal of Pharmacology 149: 393-404) and can be used White blood cells, CD4+ sputum cells and endothelial cells (www.genecard.org 'Kalin, Κ. (1999) Journal of Immunology) detection 4 201111360

(www.genecard.org). Selective small molecule inhibitors of ρ38 ΜΑΡΚ-γ and -δ are still not available, but there is an existing compound, BIRB 796, which is known and has a ubiquitous (IX isomer weight overall inhibitory activity. ρ38 γ and ρ38 δ inhibition It can be observed at higher compound concentrations than those required for Jp38MAPKa (Guma, 19472-19479). BIRB, Y· (2005) Journal of Biochemistry “ο

It is said that the side-key (four) ΜΑρκ-induced egg changes may affect the phosphorylation site and the structure of the upstream activator site, thus impairing the acidification of p38 MApKs or JNKs. . P38 MAP kinase is thought to play an important role in many signaling pathways involved in the initiation and maintenance of chronic, persistent inflammatory diseases such as severe asthma and c〇pD. There is a lot of literature today that p38 MAP kinase is activated by various pro-inflammatory cytokines and its activation has led to the replenishment and release of other pro-inflammatory cytokines. Indeed, it has been demonstrated by some clinical studies that when patients are treated with p38 MAP kinase inhibitors, there is a beneficial change in disease activity. For example, Smith, S. J. (2〇〇6) British Journal of Pharmacology 149: 393-404 demonstrates that P38 MAP kinase inhibitors inhibit the release of TNFa (but not IL-8) by human PBMCs. It is recommended that p38 MAP kinase inhibitors be used to treat chronic obstructiveness

5 S 201111360 Lung disease (COPD). The small molecule inhibitors of Ρ38 ΜΑΡΚα/β have been shown to be derived from cells and tissues of c〇pD patients who are generally susceptible to corticosteroids (Smith, SJ (2〇〇6) British Journal of Pharmacology 149 : 393 -404) and in the animal model of life (Ander, D. c et al. (2000) 279: 895-902; Nas, p. et al. (2006) European Journal of Pharmacology 544: 160-167; Medici J. et al. (2008) Journal of Pharmacological Experimental Therapy 324: 921-929) effectively reduces various parameters of inflammatory effects. Aruson and colleagues also advocated the possibility that ρ38 ΜΑΡΚα/β involves corticosteroid sensitivity by reducing the binding affinity of the nuclear adrenal glucocorticoid receptor (GR) (Arushen, Ε. et al., (2002) Allergy Journal of Clinical Immunology, 109: 649-657). Clinical trials using various p38 MAP kinase inhibitors, including AMG548, BIRB 796, VX702, SCI0469 and SCI0323, are described in Li et al. (2005) Modern Medicinal Chemistry 12: 2979-2994. COPD is said to be a symptom in which this potential inflammatory effect is reported to be substantially anti-inflammatory effects against inhaled corticosteroids. Therefore, the priority goal of treating COPD is to develop an interventional effect that simultaneously has an inhaled anti-inflammatory effect and has the ability to increase the sensitivity of the lung tissue of a COPD patient against inhaled corticosteroids. The latest publication of Merkadu et al. (2007; American Thoracic Society Abstract A56 demonstrates that Silencing ρ38 γ has the potential to restore sensitivity to corticosteroids. Therefore, the use of p38 MAP kinase inhibitors in the treatment of COPD and severe asthma may have “Double” benefits. There is now a physical evidence that the initial deterioration of the 201111360 patients with asthma and/or COPD is strongly involved in the role of respiratory virus infection. Deterioration needs to increase the intensity of treatment in order to establish control of disease symptoms. If severe, worsening may inevitably lead to hospitalization or death at the end of the day. The viruses that usually accompany deterioration include rhinovirus, influenza and respiratory viruses. The reaction of cells to these viruses is nowadays. It is known to include upregulation of ICAM1 (intercellular adhesion molecule 1) and release of cytokines, as well as replication of viral particles. Some studies have entered the effects of p38 MAP kinase inhibitors on these viral responses and some reports suggest protection The effect can be speculated using p38 MAP kinase inhibitors. Special 'some reports suggest that by virus- The inhibition of the induced ratio can be achieved in the test tube using the known compound SB2〇358〇. It is worth noting that the inflammation caused by the nasal scales is reduced and the virus is re-pre-clinical before the organism (10) + still _ significant The effect of the redness of the agent is red. However, the pattern of the popular sexy f and the day of the mouse (10) in the mouse is fully established. If the network is used to suppress the ship: the main obstacle to the disease is It has been observed in patients (± is sufficient to include more than all those compounds that are specifically mentioned above = in the clinical development of the disease still need to confirm and develop treatment _; (4), has been changed more effectively; The object of the invention is to provide a compound of the invention: a compound of the invention which exhibits good anti-i=P38 MAP kinase 201111360. [Invention] According to the invention, a compound of formula (1) is provided.

Wherein R1 is a Ci_6 alkyl group, which is optionally substituted by a hydroxyl group; R2 is a hydrazine or a Ci-6 alkyl group, which is optionally substituted by a hydroxyl group; R3 is hydrazine, Ci-6 alkyl or C〇 _3 alkyl C3-6 cycloalkyl;

Ar is a naphthyl or phenyl ring which may be optionally selected from one or more (for example '1 or 2') independently selected from Ci-6 alkyl, d-6 alkoxy, amine, Cl-4 one or two - Substituted by a group of an alkylamino group; X is a 5 or 6 membered heteroaryl group containing at least one nitrogen atom and optionally including 1 or 2 other hetero atoms selected from the group consisting of ruthenium, S and N; : a) a saturated or unsaturated, branched or unbranched alkyl chain in which at least one carbon (for example 1, 2 or 3 carbons, suitably i or 2, in particular 1 carbon) is selected from 0, N, Substituted by a hetero atom of s(〇)p, wherein the chain is optionally independently selected from one or more (eg, fluorene, 2 or 3 groups) selected from the group consisting of a keto group, a halogen, an aryl group, a heteroaryl group Substituted by a heterocyclyl group or a group of a Cs_8 cycloalkyl group. Each aryl, heteroaryl, heterocyclic or C3-8 cycloalkyl group 8 201111360 carries 0 to 3 selected from the group consisting of halogen, hydroxy, Ci-6 alkyl, Ci-6 emulsified base, C]__6 _ alkyl, Amino, C!_4 mono or di-histylamino, Ci_4 mono or di-decylamino, S(0)qCi-6 alkyl, C〇_6 alkyl C(0)d_6 alkyl or a substituent of a C 〇 6 alkyl C(〇)Ci_6 heteroalkyl group, with the proviso that the atom directly bonded to the carbonyl group in -NR3C(0)_ is not an oxygen or sulfur atom; and b) C〇_ An octyl-heterocyclyl group comprising at least one (eg 1, 2 or 3, suitably 1 or 2, in particular 1 heteroatom) selected from the group consisting of hydrazine, N, and S Atom, and optionally, one, two or three independently selected from the group consisting of halogen, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 halogen alkyl, amine, Ci_4 mono and di-alkylamino, Ci_4 Or a group of a di-fluorenylamino group, a S(0)qCi-6 alkyl group, a C〇-6 alkyl C(〇)Ck alkyl group or a c〇_6 alkyl C(0)Ci_6 heteroalkyl group Substituted; and P is 0, 1 or 2; q is 0, 1 or 2 pharmaceutically acceptable salts thereof, including all stereoisomers, tautomers and isotopic derivatives thereof. [Embodiment] A compound of the formula (I) is provided in one aspect:

S 201111360

Ν Ar-〇-X-Ν-C-Q Η Ι3 R3 (Ο ο where Rl is a Cl-6 alkyl group which is optionally substituted by a hydroxyl group 'R2 is a hydrazine or a C1-6 alkyl group' The ground is replaced by a hydroxyl group; R3 is hydrazine, Cl-6 leuntyl or C〇-3 alkyl C3-6 cycloalkyl,

Ar is a naphthyl or phenyl ring, one of which may be optionally exemplified by one or more groups independently selected from the group consisting of C1 -6 • 基 ''C1 _6 alkoxy, amine, C1 _4 mono or di- aryl amine Substituted; X is a 5 or 6 membered heteroaryl group containing at least one nitrogen atom and optionally including 1 or 2 other heteroatoms selected from 0, S and N; Q is selected from the group consisting of: a) saturated or unsaturated a branched or unbranched Ci_i chain, wherein at least one carbon (eg 1, 2 or 3 carbons) is replaced by a hetero atom selected from the group consisting of 〇, ν, S(〇)p, wherein the chain is arbitrarily Substituted by one or more groups selected from a keto group, a halogen, an aryl fluorene, a heteroaryl group or a heteroalkyl group, each aryl, heteroaryl or heterocyclic group carries a hydrazine To 3 (tetra), Cl_6 alkyl, Cl_6 alkoxy, Cl_6_alkylamino, (^_4 mono or di-alkylamino substituent, soil::: condition is in ·nr3c(〇)_ The direct bond in the middle is not sulphur; and the original 201111360 b) C 〇 8 alkyl C5-6 heteroatom group, the heterocyclic group including at least one hetero atom selected from the group consisting of ruthenium, N and S, and Optionally one or two or two independently selected from halogen C1-6 alkyl, Cl 6 alkoxy,

Substituted by a group of a Ci_6 haloalkyl group, an amine group, a Ci-4 mono- and dialkylamino group; and p is 0, 1 or 2; or a 4-acceptable salt or solvate thereof, including all thereof Stereoisomers and tautomers. As used herein, alkyl is a straight or branched chain, unrestricted, such as mercapto, ethyl, n-propyl, isopropyl, butyl, n-butyl and t-butyl. In one embodiment, alkyl refers to a linear alkyl group. The alkoxy group as used herein means a linear or branched alkoxy group such as a decyloxy group, an ethoxy group, a propoxy group or a butoxy group. The alkoxy groups used herein are also extended to the examples wherein the oxygen atom is located in the alkyl chain, for example, -Ci_3 alkyl OCi_3 alkyl, such as -CH2CH2OCH3 or -CH2OCH3. Thus, in one embodiment, the alkoxy group is bonded to the remainder of the molecule via a carbon bond. In one embodiment, the alkoxy group is bonded to the remainder of the molecule via an oxygen group, such as a _c〇 alkyl Od-6 alkyl group. In one embodiment, the disclosure is directed to a linear alkoxy group. As used herein, heteroalkyl means a branched or straight chain alkyl group wherein one or more, such as 1, 2 or 3 carbons, are replaced by a heteroatom selected from N, hydrazine or S(0)q, Where q represents 〇, 1 or 2. The heteroatom can replace primary, secondary or tertiary carbon, that is, for example, if technically appropriate, 〇H or NH2 replaces CH3, or NH or 〇 or S〇2 replaces -CH2-, 201111360 or N replaces -CH - or branched carbon groups. As used herein, a tertyl group refers to an alkyl group having from 1 to 6 halogen atoms, such as from 1 to 5 halogens, such as per-alkyl, especially perfluoroalkyl, more particularly -CF2CF3 or CF3. .

The Cl-4 mono- or mono-arylamino group means ~NHC(0)C 1 _3 calcined as and (-NC(0)Ci_3 alkyl)C(0)Ci_3 alkyl).

The one or one-homo-based amine group of Ci-4 means -NHCi_4 alkyl and -N (Ci_4 thio) (cl-4 alkyl), respectively. C6-14 Mono- or polycyclic group As used herein, for example, having at least one ring of from 1 to 3 rings is aromatic, including stupid at least one ring is an aromatic core, which includes one or more , for example 1, 2

Base, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthyl and the like, such as phenyl and naphthyl. A heteroaryl group is a 6 to 10 membered aromatic monocyclic ring or a bicyclic ring system 12 201111360 and any one or two carbon atoms may be destroyed, apparently not used to form or retain a fluorenyl substituent. If appropriate, it may be filled with gas or a substituent. For example, r can be on carbon or on heteroatoms such as N. Examples of the miscellaneous samples include dihydropyrrole and tetrahydrogen. Pyrrole, four: two C5 heterocyclic pyrazoline, imidazole °, pyrazolidine, imidazolidinium, ketomimiline:: thiophene: Mao Shao, Wei Wei, Xing Shi,,, Dihydro (four) two losses Hexahydropyrazole, morphine, dioxane, sulfur, hydrazine, (-). - Generation "Mouth and Tessa halogen contains fluorine, chlorine, bromine or iodine, in particular fluorine, which is fluorine or chlorine. -, or bromine, especially the ketone group used herein refers to hydrazine and usually c (〇) The C 3 -8 cycloalkyl group used herein means a saturated or partially unsaturated non-aromatic ring containing 3 to 2 homogens.

Ci-i 〇 alkyl includes c2, c3, C4, C5, C6, C9 and (^ and (:1〇, 8, or C7 C〇_8 alkyl includes Ci, C2, C3, C4, C5, And C〇 and Cg. Associated with saturated or unsaturated, branched or unbranched c:Ul decane, at least one carbon (eg 1, 2 or 3 carbons, 2 uppers, especially 1) is selected from the group consisting of hydrazine, N, S(0)p; the second generation, wherein the chain is arbitrarily selected by one or more independently of the fluorenyl group, halogen, aryl group, heteroaryl Substituting a group of groups or a group of a heterocyclic group to a group I, it is clear to those having ordinary knowledge in the art, if

S 13 201111360 Technically appropriate, heteroatoms can replace primary, secondary or tertiary carbons, ie CH3, -CH2- or -CH- or branched carbon groups. In one embodiment, the present invention provides a compound of formula (I) wherein R1 is decyl, ethyl, propyl, isopropyl, butyl or tert-butyl 'particularly ethyl, isopropyl A base or a third butyl group such as a third butyl group. In one embodiment, R1 is -C(CH3)2CH2〇H. In one embodiment, R2 is fluorenyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl, especially fluorenyl. In one embodiment, R2 is -CH2〇H. In one embodiment, R2 is at the 2, 3, or 4 position (i.e., the ortho position or para position), particularly on the para position (4). In one embodiment, Ar is replaced by i or two groups, and in one embodiment, Ar is armored. In one embodiment, Ar is substituted with a substituent. In one embodiment, the heart is replaced by i or 2 groups. In one embodiment, the core is a phenyl group, which is optionally 1 or 2 independently selected from the group consisting of Cl_3 filaments or leuco oxy groups, such as tolyl, dimethyl ketone', p-methoxybenzoic acid, di, oxygen Substituted by a stupid or methoxy-methylbenzene substituent. The benzene surface may, for example, be bonded to the nitrogen of the urea and bonded to the group L via a carbon 4 bond. In such cases, any one or two substituents selected from the group consisting of Cl_3 filaments or such as a silk group may be located at any position in the aromatic ring, such as at position 2 or at position 3 or at positions 2 and 3 or At positions 2 and 6 or at positions 3 and 5. Embodiments covering other possible site isomers (IV) iGisGm (10)) 201111360 also form aspects of the present disclosure. In one embodiment, R3 is deuterium. In one embodiment, R3 is methyl, ethyl, n-propyl or propyl. In one embodiment, p is 0 or 2. In one embodiment, the X system is selected from the group consisting of pyrrole, oxazole, thiazole, isoindole, sodium saliva, guanidine, isoxazole, $ diazole, d-till, spray bite, 吼° well, or 1,2 , 3 and 1,2,4 triazoles, for example, pyrazoles, isoindole, oxadiazole, pyridine, argon, pyrimidine, pyridin, or hydrazine, 2,3 and hydrazine, 2,4 triazole, especially It is pyrimidine, imidazole or pyridine, and especially pyridine or pyrimidine, more specifically 17-bit bite. In one embodiment, 1, 2, 3 or 4 carbon atoms are replaced by a heteroatom independently selected from 0, N, S(0)p. In one embodiment, The hetero atom of the carbon chain fragment of Q which is substituted for carbon is selected from N and Ο. In one embodiment, Q is a saturated or unsaturated, branched or unbranched Cu alkyl chain or a d_6 alkyl chain, at least one of which The carbon is replaced by a hetero atom selected from the group consisting of hydrazine, -N, S(Q)p. Alternatively, in this embodiment, the alkyl chain may be a C2-8 alkyl group or a C3-6 alkyl group, such as a C4 alkyl group or C5 alkyl group. In one embodiment, the nitrogen atom in the alkyl chain is directly bonded to the carbonyl group of the fragment -NR3c(0) and may, for example, be a terminal amine group. In one embodiment , Q represents Cl_6 alkyl NH2 or NH2.

15 S 201111360 In one embodiment, Q represents _NHCl_6 alkyl, such as _NHCH3 or -NHCH2CH3 or -NHCH(CH3)2. In one embodiment, 'fragment q is a saturated or unsaturated, branched or unbranched C 1-1 alkyl group chain, wherein at least one carbon (eg, 丄, 2, 3 or 4 slaves, especially 1 or Two carbons are replaced by a hetero atom selected from 〇, N, s(〇)p, for example, in this way a stable N_mercapto group 'NR3C(〇)Q is obtained, wherein the chain is arbitrarily Substituted by one or more groups selected from a keto group, a halogen, an aryl group, a heteroaryl group or a heterocyclic group, each aryl, heteroaryl or heterocyclic group carries a hydrazine to 3 independently selected from the substituents listed in the substituents of the compound of the above formula (I), such as halogen, alkyl, Cl-6 alkoxy, Ci-6 haloalkyl, amine, C1-4 mono or dialkylamine And Cl_4 mono or di-decylamino group. In one embodiment, the latter chain is optionally substituted with one or more groups selected from the group consisting of a keto group, a halogen, an aryl group, a heteroaryl group or a heterocyclyl group, each aryl group, a heteroaryl or heterocyclyl group carrying a substituent selected from the group consisting of halogen, Ci-6 alkyl, Cl-6 alkoxy, Cl-6 functional group, amine group, and cl-4 mono or dialkylamino group . In one embodiment, Q is Ci_4 alkyl-V-R4, such as Cl 3 alkyl _V-R4, wherein: - V is a hetero atom selected from NRv, hydrazine or s(0)p; Ci_3 alkyl; R4 is fluorene or -Cu alkyl, and p is as defined above, with the proviso that the total length of the alkyl chain is not more than 1 carbon atom, including the substituted hetero atom and the resulting group Q is stable. Group, example 201111360 such as '-CH2SCH3, -CH2SO2CH3, -CH2NHCH3, -CH2N(CH3)2, -C(CH3)2NHCH3, -CH(CH3)N(CH3)2, -(CH2)3CHNHCH3, -(CH2 3N(CH3)2, -CH2〇H, -CH2〇CH3, -CH(CH3)OCH3, or -(CH2)2〇CH3. In one embodiment, 'Q is Ci_3 alkyl-V-(Ci_3 alkyl-Z-R5)k' such as Ci_3 alkyl-V-(C2-3 alkyl-Z-R5)k wherein:

V is a hetero atom selected from ruthenium, osmium, 0 or S(0)p, such as N or NH (wherein k = 2, V will be selected from N, or where k = 1' is especially NH In case, it will be selected from ΝΗ, 0 or S(0)p); Z is independently selected from NH, 0 or S(0)p; R5 is Η or -Ci_3 alkyl; k is an integer 1 or 2 (eg 1) And P is as defined above, with the proviso that the total length of the alkyl chain does not exceed 1 碳 carbon atoms, including the substituted hetero atom and the resulting group Q is a stable group. Q suitably Ci_3 alkyl-V-Cualkyl-OCH3, for example, Ci_3 alkyl-V-C2-3 alkyl-OCH3 such as Ci_3 alkyl-V-(CH2)2〇CH3, especially -CH2〇(CH2 2〇CH3 and CH2S(CH2)2OCH3, or -CH2NH(CH2)2〇CH3, Ci_3 alkyl-V-(Ci-3 alkyl-〇CH3)k, where k represents 2, such as cl-3 alkyl -V-(C2-3 alkyl_〇CH3)k is as -CH2N[(CH2)2〇CH3]2. 201111360 In one embodiment 'Q is Ci-3 alkyl-V-Ci_2 alkyl _Z-Ci-2 alkyl-Y-R6, or Cl_3 alkyl-V-C2-3 alkyl-Z-C2- 3 alkyl_Y_R6, wherein ν, ζ & γ are independently heteroatoms selected from NH, 〇*s(〇)p, R6 is Η or methyl, and Ρ is as defined above, but the τ condition is a burnt bond The total length is no more than 1 carbon atom, including the substituted hetero atom and the resulting group Q is a stable group. Q is suitably -CH2V(CH2)2〇(CH2)2〇CH3, such as -CH2〇(CH2)2〇(CH2)2〇CH3, -CH2NH(CH2)2〇(CH2)2〇CH3, or -CH2S (CH2) 2 〇 (CH2) 2 〇 CH3. In one embodiment 'Q represents -NR7R8 and _NR3c(〇)Q forms urea' wherein R7 and R8 independently represent a saturated or unsaturated, branched or unbranched alkyl chain of hydrogen or Cl_9, wherein one or more carbons, For example, 丨, 2 or 3 are optionally replaced by a hetero atom selected from 〇, N or S(0)p. The chain is optionally substituted by a group of one or more independently selected from a keto group, a halogen, an aryl group, a heteroaryl group, a heterocyclic group or a c3-8 cycloalkyl group. The aryl, heteroaryl or heterocyclyl group carries hydrazine to 3 substituents independently selected from the substituents listed in the compounds of the preceding formula (I), such as i, Ci-6 alkyl, Ci-6 alkoxy , Cl_6 haloalkyl, amine, Cl-4 or monoalkylamino and C14 mono or di-decylamino, but with π conditions, the total length of the alkyl chain is not more than 1 carbon atom, including alternative The ruthenium atom and the resulting group Q are stable groups. 201111360 In one embodiment 'Q represents -NR7r8 and _NR3C(0)Q forms a vein 'where R7 and R8 independently represent a hydrogen or Ci_9 saturated or unsaturated, branched or unbranched alkyl chain, one or more carbons For example, 丨, 2 or 3 are optionally replaced by a hetero atom selected from 〇, N or s(〇)p. The chain is optionally substituted by one or more groups independently selected from the group consisting of a keto group, a halogen, an aryl group, a heteroaryl group or a heterocyclic group, each aryl, heteroaryl or heterocyclic group. The group carries hydrazine to three substituents independently selected from the substituents listed in the compound of the preceding formula (I), such as halogen, Cl_6, Ki-6 alkoxy, Ci-6 halogenalkyl, amine, Ci-4 a mono- or di-alkylamino group and a Ci_4 mono or di-decylamino group, with the proviso that the total length of the alkyl chain does not exceed 10 carbon atoms, including the substituted hetero atom and the resulting group Q is a stable group. group. In this urea embodiment, R7 represents hydrogen in one sub-example. Examples of urea include those wherein R7 and R8 are both hydrogen and Q is -NH2, or wherein Q is -NHCH3 or -N(CH3)2, for example, fragment -NR3c(0)NH2 or -NR3c(0) NHCH3 or -NR3C(0)N(CH3)2. Examples of the urea having a hetero atom in the alkyl chain include those wherein Q is: -NH(CH2)2〇CH3 or -N[(CH2)2〇CH3)]2. In one embodiment, Q represents -NHC2-6 alkyl hydrazine Cl-3 alkyl, such as -NHCH2CH2OCH3. Examples of the urea having a keto substituent include those wherein Q is -NHCH2C(0)NH-C2_3 alkyl-XhClG alkyl, wherein X! 201111360 is a hetero atom selected from N, 0 or S(0)p and p is defined as before. Examples of the latter include those in which Q is -NHCH2C(0)NHCH2CH2〇CH3. Thus, in one embodiment, q represents -NHCi_4 alkyl C(0)NHC2 alkyl 0CH3 , such as -NHCH2C(0)NHCH2CH2〇CH3. In one embodiment, Q represents -NHCi_4 alkyl C(0)RQ, wherein RQ is selected from 0H or -NR'R", and R' is hydrogen or Ci_3 alkyl and R" is hydrogen or Ci_3 alkyl, For example, -NHCH2C(0)0H, -NHCH2C(0)NH2 or -NHCH2C(0)NHCH3 such as -NHCH2C(0)0H or ·NHCH2C(0)NHCH3. In one embodiment, Q represents -NHCi_4 alkyl C(0)0Ci-3 alkyl, such as -NHCH2C(0)0CH2CH3. In other sub-embodiments of urea, Q represents -N-R9Ci_3 alkyl-V-(Cl_3 alkyl_Z-Rl〇)k, for example, -N-R9C2-3 alkyl-V- (C2-3 -Z-Rl〇)k where: V represents N, NH, 0, S(0)p; Z represents NH, 0, S(0)p; k is an integer 1 or 2; P is an integer 0, 1 or 2 R9 represents hydrazine or Ci_3 alkyl-V-(Ci_3 alkyl-Z-Rl〇)k such as C2-3 alkyl-V-(C2-3 alkyl_Z-R10)k; and R10 is Η or Cm An alkyl group, such as (^_3 alkyl; but with the proviso that the total length of the alkyl chain includes no more than 10 carbon atoms in the substituted heteroatom, and the resulting group Q is a stable 201111360 group. In one embodiment, Q is a saturated or unsaturated, branched or unbranched cM 〇 alkyl chain in which at least one carbon is replaced by a hetero atom selected from the group consisting of 〇, N, and S(〇)p, wherein the chain is carried by G to 3 substituents, for example 1, 2 or 3, such as 1 or 2 aryl groups independently selected from the substituents listed in the substituents of the compound of formula (1), such as from halogen, Ci-6 alkane a group, a Ci-6 alkoxy group, a Ci-6 haloalkyl group, an amine group, and a Cl-4 mono or di-alkylamino group and a Ci_4 mono or di-decylamino group, such as saturated or unsaturated And a branched or unbranched C 〇 1 alkyl chain in which at least one carbon is replaced by a hetero atom selected from the group consisting of Ο, N, and S(0)p 'where the chain is carried with 〇 to 3 substitutions The radical ', for example 1, 2 or 3, such as i or 2 substituents independently selected from the group consisting of halogen, Cl-6 alkyl, Ci-6 alkoxy, Ck haloalkyl, amine and Cl_4 mono or di-alkylamino Substituted by an aryl group. In one embodiment, the aryl group is a phenyl group, such as a substituted phenyl group or an unsubstituted phenyl group. In one embodiment, Q represents -NHC〇_6 alkane. A phenyl group such as -NH phenyl or NH benzyl. Fragment -NR3c(0)Q wherein Q includes a substituted benzyl group includes: -NR3c(0)CH2NHCH2C6H4(〇CH3) such as -NHC(0)CH2NHCH2C6H4 (0CH3), for example, when the oxime substituent is in the ortho, meta or para position, such as in the para position. In one embodiment, Q is a saturated or unsaturated, branched or unbranched Cm 〇 alkyl chain , wherein at least one carbon is selected from the group consisting of Ο, N, and

21 S 201111360 S (〇)p replaced by a hetero atom 'where the chain is carried to 3 (eg 1, 2 or 3, such as hydrazine or 2 substituents) independently selected from the former formula (I Substituting a heteroaryl group of a substituent in a compound-related substituent for example 'halogen, Cl-6 alkyl, d-6 alkoxy, Cl-6 alkylamino, Cl-4- or di-alkylamino and Ci_4 Or a di-mercaptoamine group, such as a saturated or unsaturated, branched or unbranched Ci_i alkyl group, wherein at least one carbon is replaced by a hetero atom selected from the group consisting of ruthenium, N, and S(0)p, wherein The chain is carried with hydrazine to 3 substituents, for example 1, 2 or 3, such as 1 or 2 selected from halogen, Ci-6 alkyl 'Ci-6 oxime, Cl 6 alkylamino, Ci- Substituting a heteroaryl group of a substituent of a mono- or di-alkylamino group. In one embodiment, the heteroaryl group is selected from the group consisting of thiophene, oxazole, thiazole, isothiazole, imidazole, pyrazole, isoxazole, isothiazole, oxadiazole, 1, 2, 3 or 1, 2 , 4 triazole, acridine, hydrazine, pyrimidine, pyridin, and especially pyridine and pyrimidine, especially pyridinium. In one embodiment 'Q represents -NHd_6 alkylheteroaryl, for example -NH(CH2)3 imidazolyl or -NHCH2isoxazole, wherein isoxazole is optionally substituted by, for example, -NHCH2isoxazole (CH3) . In one embodiment, Q represents -NHCM alkyl (:(0) Νίκ:1_3 alkylheteroaryl, such as a nitrogen-containing heteroaryl fluorene or a nitrogen- and oxygen-containing heteroaryl group, more particularly -NHCH2C (〇) NHCH2CH2 ° is a pyridyl group, especially when the acridine group is bonded via carbon, such as a pyridyl-4-yl group or a -nhch2c(o)nhch2ch2ch2 imidazolyl group, especially when the amino group is via the nitrogen Bonding. In one embodiment, Q is saturated or unsaturated, branched or not divided. 22 201111360 = cM brothel base chain 'At least one of the carbons is replaced by cesium, N and (p) Wherein the chain is substituted with a heterocyclic group independently selected from the substituents listed in the substituent of the preceding formula (1) = (for example, π into I/' such as 1 or 2 substituents), for example, Mouth 1, Cl-6 alkyl, d_6 methoxy, Cl 6 self-alkylamino, 1:4 - or di-homo-amine and Cl_4 - or di-arylamino, such as saturated or unsaturated, a branched or unbranched Cmg chain, wherein at least one of the slaves is replaced by a hetero atom of 'N & s(0)p, wherein the chain is blocked by a heterocyclic group to 3, For example, Bu 2 or 3, 'like 1 or 2 Substituted from a substituent of S, Cl 6 alkyl, Ci 6 alkoxy, I-6 -alkylamino, Cl. 4 or di-decylamino. a ^ In one embodiment, the heterocyclic group Is selected from the group consisting of 5 or an unsaturated or unsaturated ring system comprising one or more (eg 1, 2 or 3, especially 1 or 2) heteroatoms independently selected from the group consisting of 〇, N & s , for example, tetrahydropyrrole, tetrahydrofuran, tetrahydrothiophene, hexahydropyridine, hexahydropyridinium triisofuran, 1,4-dioxane, tetrahydropyrrole and keto imidazolium, such as hydroquinone, Tetrahydrofuran, tetrahydrothiophene, hexahydropyridine, hexahydropyridinium, mazumidine, and 1,4-dioxin, especially hexahydron-bite, hexahydromorphine, and phoxim. The group may be bonded to the alkyl group of Q or to the carbonyl group of -NR3c(〇)_ via carbon or nitrogen, particularly a nitrogen atom. In one embodiment, Q is a -C〇_3 alkyl heterocycle (eg, a -coq heterocyclic group, the heterocyclyl group comprising at least one (eg 1, 2 or 3)

23 S 201111360, in particular 1 or 2 heteroatoms) selected from hydrazine, N&s and optionally arbitrarily selected from one or two or three independently selected from the substituents associated with the former compound 'eg _ 素, 1 Substituted by a group of -6 alkyl, Ci & aryl, alkyl, amine, CM mono and dialkylamine 1: dioxo or di-decylamino. Earth 1-4 In one embodiment, wherein Q is a hydrazine heterocyclic ring via a carbon bond, and is 'for example, d-bonded tetrahydro π-dean or C- 1 hexahydro (tetra) Or C. bonded 福 福 c _ c c c c 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于 于The N atom is finely occupied by t, and the work is connected by N. This embodiment provides urea, in which one urea nitrogen is embedded in - examples include, but are not limited to, N-bonds. Bayesian> The urinary bond is connected to the N-bonded or N-bonded hexahydrogen ratio well, the N-bonded hexahydropurine, the radical carries any additional c _ or ^ substituent (such as a ~methyl group ^-CH2CH2QCH3 group). In one embodiment, q is a heterocyclic group bonded via l, such as a hexahydroquinanyl group, particularly a 4-6 sulphur bite group or a hexahydrotetrazole group, for example, 4-methylhexahydroindole σ Well base. In one embodiment, 'Q represents a heterocyclyl group, a dinitrogen-containing heterolyl group II, particularly a (iv) fluorene bond, such as optionally substituted by a methyl group, which is replaced by a 4 methyl group. The sulphate D-based or hexa-(tetra)-based, or hexahydro-to-bite. In the case of a shell, Q is a _Ci alkyl group, for example, a tetrahydro σ-mercaptopurine group or a c- or a bond carrying a substituent (for example, a Cl 6 alkane 24 201111360-based substituent, such as A hexahydroindenyl sulfhydryl group of a fluorenyl or Cl_6 alkoxy substituent such as -CH2CH2OCH3). Other examples include a C- or hydrazone-bonded tetrahydropyrrolyl fluorenyl group, or a c- or hydra-bonded di-based imidazolinyl fluorenyl group (such as a 2-ketotetrahydroimidazolylmethyl group). The ring optionally carries a substituent (such as 7V·methyl or WSO2CH3). In one embodiment, Q represents a _NH heterocyclic group (wherein the heterocyclic group has 0 to 3 selected from the compounds listed in the above formula (1). Substituents in the list of substituents, such as halogen, hydroxy, C1-6 alkyl, Ci<alkoxy, Ci-6haloalkyl, amine, Cl4 mono or dialkylamino, -S(0)qCi_6 Alkyl, Ci_4 mono or di-decylamino, c〇_6 alkyl hydrazine: (0) 0-6 alkyl or C〇_6 alkyl c(〇)Cl_6 heteroalkyl), such as via Carbon is bonded to, for example, 2·hexahydropyridyl or 3-hexahydropyridine S or 4-hexahydropyridyl, in particular 丨·ethoxymethyl hexahydropyridine _4 —yl, 丨-methylhexahydropyridine- 4-Based, 1-(indolylsulfonyl)hexahydropyridine-decarboxyl or 1-(2-(2-decyloxyethoxy)ethenyl) hexahydroindenyl. In one embodiment And Q represents an -NHC^alkylheterocyclyl group, such as a nitrogen-containing heterocyclyl group, particularly one via a nitrogen bond, such as -NHCH2CH2 -NH(CH2)3, or -NH(CH2)4, whey sulphate. In one embodiment, Q represents _NHCl_6 alkyl c(anthracene) heterocyclic group (wherein the heterocyclic group carries hydrazine to 3 Substituents selected from the list of substituents listed in the compound of the above formula (1), such as halogen, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 halogenalkyl, amine, Ci_4 mono or di-alkylamino C丨·4 mono or di-decylamino, c〇_6 alkyl c(〇)Ci 6

S 25 201111360 alkyl or C〇_6 alkyl C(0)Ci_6 miscellaneous) 'for example a nitrogen-containing heterocyclyl group, especially via a nitrogen bond, such as -NHCH2C(0)-1-tetra Hydropyrrolyl, -NHCH2C(0)-1-hexahydropyridinyl, _NHCH2C(0)-4-norfosyllinyl or -NHCH2C(〇)hexahydroindole σ well group, such as -NHCH2C(0)-4 - Mercapto-1-hexahydro-π ratio alpha well base. In one embodiment, Q represents -NHCi-4 alkyl C(0)NHCi_3 alkylheterocyclyl' such as a nitrogen-containing heterocyclyl group or a nitrogen-containing and/or oxygen-containing heterocyclyl group such as -NHCH2C ( 0) NHCH2CH2 is a sulfhydryl group, particularly when the ruthenium group is bonded via a nitrogen bond. In one embodiment, Q represents a _N(Cl_3 alkyl)Cl-6 alkylheterocyclyl group, such as a nitrogen-containing heterocyclyl group, particularly via a nitrogen bond, such as -N(CH3)CH2CH2. Lin, _N(CH3)(CH2)3 suffolin or -N(CH3)(CH2)4 morpholine. In one embodiment 'Q is _Cl_3 alkyl_G_Cl_3 alkyl heterocycle, wherein G is a hetero atom selected from NH, 0 or s(〇)p, the heterocyclyl group comprising at least one (eg 1' 2 or 3, particularly hydrazine or 2 heteroatoms) selected from the group consisting of 0, N, and S heteroatoms, and optionally one or two or three independently selected from the substituents listed in the compound of the above formula (1), For example, i-, Ci-6 alkyl, Ci_6 alkoxy, Cl_6-alkyl, amine, Ci_4 mono- and di-alkylamino and Ci_4 mono- or di-decylamino such as one or two or three Substituents of the group s, d_6 alkyl, Cl-6 alkoxy, Cl-6 halogen alkyl, amine, Ci_4 mono- and di-alkylamine groups. Q is suitably a -CH2G(CH2)2 heterocyclic ring such as 〇Η2(}(〇:Η2)2tetrahydropyranyl' or -CH2G(CH2)2, or a heterocyclic group via nitrogen or 26 201111360 Carbon bond; or CH2G(CH2)2 hexahydropyranin wherein the heterocyclic group is bonded via nitrogen or carbon and optionally carries other c- or substituents (eg, a Cl_6 alkyl group such as a decyl group or a Cl alkoxy group) a substituent such as -CH2CH2OCH3); or -CH2G(CH2)2 tetrahydropyrrole, wherein the heterocyclic group is bonded via nitrogen or carbon, for example via a nitrogen linkage; or -CH2G(CH2)2 ketoimidazoline The group (e.g., 2-ketotetrahydroimidazolyl) is bonded, for example, via a nitrogen bond and optionally carries an additional C- or iV-substituent (e.g., methyl or WSO2CH3), and wherein G is 0 or NH. In one embodiment, G is Ο. In one embodiment, G is NH. In one embodiment, 'Q is a saturated or unsaturated Cuq alkyl chain' wherein at least one carbon (eg, 1, 2, or 3 carbons) is Substituting a hetero atom selected from 〇, n, S(〇)p where 'the chain is substituted by a C3-8 carbocyclic group and the alkyl group is optionally selected by one or more (eg 1 or 2) Substituted from a keto group and a halogen group. In an embodiment, the dg rabbit cyclic group carries one or more (eg 1, 2 or 3 groups) independently selected from the group consisting of halogen, hydroxy, Ci-6 alkyl, Ck alkoxy, Ci-6 halogen alkyl, amine , Ci_4 mono or di-alkylamino, Ci_4 mono or di-arylamino, alkyl, C〇_6 alkyl C(0)Cl_6 alkyl or C〇_6 decyl C(0)Ci_6 a heteroalkyl group. In one embodiment, Q represents -NHC3-6 cycloalkyl, such as -NH cyclodecyl '-NH cyclopentyl or -NH cyclohexyl. In one embodiment, aryl, A heteroaryl or heterocyclyl group carries at least one -S(0)qCi_6 alkyl substituent and optionally carries one or two

S 27 201111360 are independently selected from other related substituents as defined in the list of substituents of the compound of formula (i). In one embodiment, the 'C5_6 heterocyclic ring carries at least one _S(0)qC 1_6 alkyl substituent and optionally carries a lower or two other independently selected from the list of substituents as defined in the compound of formula (I) above. Substituent. In one embodiment, an aryl, heteroaryl or heterocyclyl group carries at least one via substituent and optionally carries one or two substituents independently selected from the list of substituents as defined in the compound of formula (I) above. Other substituents. In one embodiment, the C5-0 heterocyclic ring carries at least one hydroxy substituent and optionally carries one or two other substituents independently selected from the list of substituents as defined in the compound of the above formula (1). In one embodiment, the aryl, heteroaryl or heterocyclyl group carries at least one Ci-4 mono- and/or di-decylamino substituent and

One or two independently selected K is as defined in the compound of the above formula (1); Early month T /% In a consistent example, the C5-6 heterocycle carries at least one Cl_4, a dimethyl group substituent and optionally carries one or two independently selected compounds of the formula (I) Others in the list are substituted for an 'Example towel' filament or a heterocyclyl group, a C〇-6 alkyl group (XCOCk heteroalkyl substituent and 咅

Mutt is self-determined (d). In one embodiment, the C5-6 heterocycle carries at least one C〇, 6 alkyl 28 201111360 C(0)Ci-6 heteroalkyl substituent and optionally One or two other substituents independently selected from the list of compounds as defined in the above formula (1). In one embodiment, the f " soil, mono-heterocyclic or heterocyclic group carries at least one C〇_6 alkyl C(0)Cl_6 alkyl substituent and optionally carries one or two Independently selected from other substituents as defined in the compound of formula (1). In one embodiment, the C5-6 heterocyclic ring carries at least one c〇_6 alkyl group (:(0)(^-6 alkyl substituent and optionally carries one or two independently selected from the group consisting of the former formula (1) Other substituents in the substituents of the compound. In one embodiment t, Q represents a tetrahydrofuranyl group, a hydrazine group, a hexahydropyridyl group such as a hexahydroacridinyl group bearing a hydroxy substituent, A pyrithione such as a hexahydropyrryl group having a methyl substituent such as a tetrahydropyrrolyl group bearing a dimethylamino substituent: the ring may be via a heterogeneous*, such as Nitrogen bonding. Alternatively, the ring may be via carbon = the substituent may be, for example, the opposite of the atom to the remainder of the molecule via the ring. t & In one embodiment, Q The alkyl chain fragment does not carry any substituents. In one embodiment, the alkyl chain is saturated. In one embodiment, the alkyl chain is unbranched. In one embodiment, the alkyl chain fragment of Q carries There are 1, 2, or 3, such as 1 or 2, especially for any of the substituents. 201111360 Those with ordinary knowledge in the technical field should be very clear, such as Technically appropriate, a heteroatom can be substituted for a primary di-indenyl secondary or tertiary carbon, i.e., a CH3 di-indenyl-CH2- or -CH- group. In one embodiment, p is deuterium or 2. In one embodiment, P is 1. In one embodiment, the compounds of the disclosure include those wherein the fragment Q is: -CH20H; -CH2〇Ci_6 alkyl, specifically _CH2〇CH3; -CH2CH2OCH3; -CH20( CH2)2〇CH3; -CH(CH3)OCH3; -CH2NHCH3 or -CH2N(CH3)2; -CH2NHCH2CH2OCH3 or -CH2NHC(0)CH2〇CH3; -CH2SCH3, -CH2S(0)2CH3 or -CH2NHC(0) CH2S(0)2CH3; or -CH2NHC(0)CH2. In one embodiment, the compounds of the present disclosure include those wherein the fragment of the formula (I)-NR3c(0)Q is represented by the following: NR3c(0)CH2〇H, especially -NHC(0)CH2〇H; -NR3C(0)CH20Ci-6 alkyl, especially -NR3C(0)CH20CH3, especially -NHC(0)CH20CH3; -NR3C (0) CH20(CH2)20CH3, especially -NHC(0)CH2〇(CH2)2〇CH3; 201111360 -NR3C(0)CH(CH3)0CH3, especially NHC(0)CH(CH3)0CH3; NR3c(0)CH(CH3)NHCi_3 alkyl, especially -NHC(0)CH(CH3)NHCH3; _NR3C(0)CH(CH3)N(C1_3 alkyl)2 , especially -NHC(0)CH(CH3)N(CH3)2; NR3C(0)C(CH3)2NHCH3, especially -NHC(0)C(CH3)2NHCH3; -NR3C(0)(CH2)2 〇Ci-6 alkyl, such as -NR3c(0)(CH2)2〇CH3, especially -NHC(0)(CH2)2〇CH3; -NR3C(0)(CH2)3NHC1_3 alkyl, especially - NHC(0)(CH2)3NHCH3; alkyl)2, especially -NHC(0)(CH2)3N(CH3)2; -NR3C(0)CH2NHCi-3 alkyl, especially -NHC(0)CH2NHCH3; -nr3c(o)ch2nh(ch2)2och3, especially -NHC(0)CH2NH(CH2)2〇CH3; -NR3c(0)CH2SCH3, especially -NHC(0)CH2SCH3; -NR3C(0)CH2S(CH2 ) 20CH3, especially -NHC(0)CH2S(CH2)2〇CH3; -NR3c(0)CH2S(CH2)2〇(CH2)2〇CH3, especially -NHC(0)CH2S(CH2)20(CH2 2〇CH3, -NR3c(0)CH2S0CH3 'Special ij is -NHC(〇)CH2SOCH3 31 201111360 -NR3c(0)CH2S(0) 2CH3 , especially -NHC(0)CH2S(0)2CH3 ; _NR3c( 0) CH2N[(CH2)2〇CH3]2, especially -NHC(0)CH2N[(CH2)2〇CH3]2 » -NR3C(0)NH2, especially -NHC(0)NH2; -NR3C( 0) NHC1_9 alkyl, such as NR3C(0)NHC1_7 alkyl, especially -NHC(0)NHCH3'-NR3c(0)N(Ci-4 alkyl)d_5 alkyl, especially -NHC(0)N ( CH3)2; or NR3C(0)NHCh2CONH(CH2)2〇CH 3, especially -NHC(0)NHCH2CONH(CH2)2〇CH3. In one embodiment, the compounds of the present disclosure comprise a compound of formula (1) wherein the fragment -NR3C(0)C〇-8 alkylheterocyclyl is represented by the following: -NHC(0)-(tetrahydroalpha Oryl), such as -NHC(0)-(tetrahydropyran-4-yl): -NHC(0)-(morphinyl), such as _NHC(0)-(4-folfyl) or -NHC(0)-(3-isofenyl); -NHC(0)-(tetrahydropyrrolyl), such as -NHC(0)-(tetrahydropyran-3-yl); -NHC(0)- (hexahydropyrrole), such as -NHC(0)-(hexahydropyridinium small base); -NHC(O)-(mercaptohexahydrocarbyl), such as -NHC(0)-(4 -methylhexahydroindole-1-yl); -NHC(0)-[(methoxyethyl)hexahydropyridinium], such as _nhc(〇)_[4_(2_ 曱oxy B )) hexahydropyrrol-1-yl]; 32 201111360 -NHC(0)-(ketotetrahydroimidazolyl), such as _NHc(〇)-(2-keto^azolyl)' is especially -NHC (0)-(2-ketotetrahydroimidazol-1-yl); -NHC(0)CH2-(tetrahydropyranyl), such as _NHC(0)CH2-〇^piperidin-4-yl ); -NHC(0)CH2-(?福"林基)' such as _nhc(〇)CH2_(4 _ base); ♦祙

-NHC(0)CH2-(tetrahydropyrrolyl), such as _NHC(0)CH2-(tetrahydrol. each -1-yl); D-NHC(0)CH2-(hexahydrocaline) 'eg _NHC(0)CH2_(hexahydropyrrolidin-1-yl); -NHC(0)CH2-(mercaptohexahydrogen 0 to sputum base), w_nhC(0)CH2-(4-methyl 6 atmosphere ° ratio well-1-base); -NHC (0) CH2-[(methoxyethyl) hexahydro π & π well base], such as -NHC (0) CH2-[4-(2· Methoxyethyl)hexahydropyrazine_丨_yl]; -NHC(0)CH2SCH2CH2·(morpholinyl), such as -NHC(0)CH2SCH2CH2-(4-morpholino), or -NHC (0) CH2SCH2CH2-(3-isfosyl); and _NHC(0)CH2S〇2CH2CH2-(ifufuyl), such as NHC(0)CH2S02CH2CH2-(4-? Nhc(o)ch2so2ch2ch2-(3-folfyl). In one embodiment, the compounds of the present disclosure include a compound of formula (1), wherein Q is: -(tetrahydro σ thiopyranyl)', such as -(tetrahydro-ΖίΓ-n-n- 4-pyrene-(folphibenyl) ), such as - (4-ifu Weiji);

S 33 201111360 - (tetrahydro σ ratio p base), such as - (tetrahydropyrene ratio ° -1 base); _ (six mice. than 13 well base) 'such as - (six rats σ ratio σ well - 1-yl), _(indenyl hexanitrogen σ ratio 3 well base) 'such as -(4-mercapto hexanitrogen ratio σ well-1 -yl), -(methoxyethyl)hexahydropyrrole , for example, -4-(2-decyloxyethyl)hexahydropyridinium-1 -yl, -^^^tetrahydrofuranyl group as broad as -^^^tetrahydro-^^-唆-- ); -CH2-(fofofyl), such as -CH2-(4-fosfyl); -CH2_ (four to 0 bases), such as -CH2-(tetrahydroanthracen-11) -CH2-(hexahydropyrrole), such as -CH2-(hexahydropyridin-1-yl); -CH2-(mercaptohexahydropyrryl), such as -CH2-(4- Mercaptohexahydropyrazine-1 -yl); -CH2-[(decyloxyethyl)hexahydropyranyl], such as -CH2-[4-(2-methoxyethyl)hexaza-α ratio 〇井_1_基], -CH2NHC(0)-tetrahydrofuran, such as -CH2NHC(0)-(tetrahydro-2//·piperidin-4-yl); -CH2NHC(0)-isfosyl, Such as -CH2NHC(0)-(4-morpholino)-CH2NHC(0)-(hexahydropyrrole), such as -CH2NHC(0)-(hexahydropyrazine-1-yl), and -CH2NHC (0)-(mercaptohexahydropyrrole), such as -CH2NHC(0)-(4-methyl Six rats 0 to 0 well - I-base). In one embodiment of fragment Q, a saturated or unsaturated, branched or unbranched Cm〇 alkyl chain in which at least one carbon is replaced by a hetero atom selected from -0, -N, S(0)p is selected From: -CH2〇CH2-, -CH2NHCH2-, -CH2NH-, and -CH2OCH2CH2-. Such fragments 34 201111360 γ are optionally interrupted by an aryl group, a heteroaryl group, a heterocyclyl group or a C3_8 % alkyl group, such as an aryl group or a heteroaryl group, a heterocyclic group. The group is defined as the former fragment Q. In one embodiment, the disclosure is directed to a compound of formula (IA).

0 -H-Q Bu. 〇[ 0A) where ' Rl,R2 'Ar, R3 and q are as defined above. In other embodiments, the disclosure is directed to a compound of formula (IB): Η

RK.X

Wherein 'R1' R2 'Ar 'R3 and Q are as defined above. In yet another embodiment, the disclosure is directed to a compound of formula (IC):

S 35 201111360 wherein ' Rl, R 2 'Ar and R 3 are as defined above and z represents a saturated or unsaturated, branched or unbranched Cl_9 alkyl chain, wherein at least one carbon (eg 1, 2 or 3 carbons, suitably i Or 2, particularly 1) is replaced by a hetero atom selected from hydrazine, N, S(0)p, or a C〇-7 alkyl-heterocyclic ring containing at least one (eg 1 , 2 or 3 'appropriate 1 or 2, especially 1 heteroatom) selected from heteroatoms of hydrazine, N and S, and optionally exemplified by one or two or three independently selected from the formula (I) Substituting substituents for the compound, such as halogen, Cl-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, amine, Ci_4 mono and di-alkylamino groups. In one embodiment of formula (1C), z is OCH3 or -OCH2CH2OCH3. In one embodiment of formula (1C), Z is -SO2CH3. In one embodiment of formula (1C), Z is -NRArB, wherein rA and RB are independently selected from hydrogen, Ci-6 alkyl, and C3-6 alkoxy (where alkoxy is not bonded via oxygen) such that, for example, Z Represents -NH2, -NHCH3, -N(CH3)2 or -NHCH2CH2OCH3. In one embodiment of formula (1C), Z is -S(0)nCH3, where n is an integer of 0, 1 or 2, such as 0 or 2. In one embodiment of formula (1C), hydrazine represents a 5 or 6 membered heterocyclic ring containing at least one (eg 1, 2 or 3, suitably 1 or 2 'particularly 1 heteroatom) a hetero atom selected from the group consisting of ruthenium, osmium, and S, and optionally arbitrarily selected from one or two or three groups selected from the substituents listed in the compound of the above formula (1), such as _, C1 thiol, 36 201111360

Ci-6 alkoxy, Ci_6 haloalkyl, amine, Ci_4 mono- and di-alkylamino group, for example: morphine B-based (especially via nitrogen bonding) or tetrahydropyranyl, or The hexahydropyrazine (particularly via nitrogen bonding) is optionally substituted with -CH3 or -CH2CH2OCH3 on the second nitrogen. In one embodiment, the disclosure is directed to a compound of formula (ID):

Wherein R1, R2, Ar and R3 are as defined above and R4 and R5 independently represent hydrogen, Ci-6 alkyl, or R4 and R5 together with the nitrogen to which they are attached represent any optionally containing 5 or more heteroatoms selected from 〇, N and S a 6-membered heterocyclic ring wherein the heterocyclic ring is optionally selected from one or two or three independently selected substituents listed in the compound of the above formula (1) such as halogen, Ci-6 alkyl, Ci-6 alkoxy, cl-6 Substituted by haloalkyl, amine, Ci_4 mono- and di-alkylamino groups. In one embodiment of the compound of formula (ID), the group _NR4r5 represents -NH2, -NHCH3 or NHCH2CH3. In one embodiment of the compound of formula (ID), _NR4R5 represents a whey sulphate or a hexahydroquinone σ well.

S 37 201111360 This disclosure relates to an alternative embodiment of the formula (IE):

Where ' Rl, R2, αγ and —

Het ^ ^ -ν' °

Het represents a 5 or 6-shell heterocycle, l 1 0 , ^ , μ heterocyclyl oxime contains at least one (eg 1, 2 or 3, suitable for helmeting, 1 or 2 Yamada horses, especially 1 hetero atom) a self-deuterium, hydrazine, and S hetero; g jl a / fluorene atom, and optionally one or two or two independently selected from the related substituents listed in the compound of the above formula (1), such as a phytosin Ci_6 alkyl group, Ci_6 Substituted by an alkoxy group, a Ci_6 haloalkyl group, an amine group, a Cl-4 mono- and di-alkylamino group. In one embodiment of the compound of formula (IE), Het is a ruthenium group or a tetrahydrocarbyl group. In one embodiment, the compound is: Ν-(4_(4-(3.(3-tert-butyl-1-p-tolyl κ azole-5-yl) ureido)naphthalen-1-yloxy) Bite-2-yl)-2 methoxyethoxy)ethylamine; Ν-(4-(4·(3_(3-tert-butyl-p-p-tolyl-t-pyrazole-5-yl) ) urethyl) naphthalene small oxy-based keto-2-yl)tetrahydro-2-indole + nan-4 amide; Ν_(4_(4_(3_(3_t-butyl-1-p-tolyl^) Benzene _5_yl) ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-(methylthio)acetamidamine; 38 201111360 N-(4-(4-(3-( 3-tert-butyl-1-p-tolyl-1//-carbazol-5-yl) fluorenyl)-n-yl lactyl) ° 定-2-yl)-3-decyloxy Propylamine, N-(4-(4-(3-(3-tert-butyl-1-p-phenylene-1H-pyrazol-5-yl)) urethyl)N--1-yl lactyl Dtba-di-2-yl)-2-yl-ethylamine, N-(4-(4-(3-(3-isopropyl-1-p-phenyl)-1H-pyrazole-5-yl) Ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-decyloxyacetamide; N-(4-(4-(3-(3-ethyl-1-p-nonylbenzene) -1H-carbazol-5-yl)ureido)naphthalen-1-yloxy)α-pyridin-2-yl)-2-methoxyacetamide; Ν-(4-(4-(3) -(3-t-butyl-1-p-tolyl-1Η-pyrazole-5-yl) month Urinyl)na-1-yl lactyl)° ratio 0-but-2-yl)-2-indole-ethylamine, N-(4-(4-(3-(3-(l-hydroxy-2)) - mercaptopropan-2-yl)-1-p-tolyl-1 oxime-oxazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)-2-methoxy B Indoleamine; Ν-(4-(4_(3-(3·3,6-tetrakis-4-(trimethyl)phenyl)-lH-atba Sodium-5-yl) glandyl)-1-yloxy) ° 咬-2-yl)-2-methoxyacetamide; N-(4-(4-(3-(3-) Tributyl-1-p-phenylene-1H-pyrazol-5-yl) urethral)N- 1 1 yloxy) π-biti-2-yl)-2-isfene , Ν-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1-pyridin-5-yl) ureido)naphthalen-1-yloxy)pyridinium -2-yl)-(dimethylamino)acetamide; Ν-(4-(4-(3-(3-tert-butyl-1-p-phenylene-1Η-pyrazole-5-) Base) benzyl-1-methyloxy"pyridin-2-yl)-2-(2-methyllacylethylamino)acetamide;

39 S 201111360 N-(4-(4-(3-(3-Tert-butyl-1-p-tolyl-1H-pyrazole-5-yl))ureido)naphthalen-1-yloxy)<»Bite-2-yl)-2-glycosylacetamide; N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazole·5-yl) Ureido)naphthalen-1-yloxy) °pyridin-2-yl)-2-(2-decyloxyethylamino)acetamide; team (2-(4-(4-(3) -(3-tert-butyl-1-p-tolyl-lH-nbazole-5-yl) ureido)naphthalen-1-yloxy)° than biti-2-ylamino)-2-g Benzyl)tetrahydro-2H-pyran-4-carboxyguanamine; Ν-(2-(4-(4-(3·(3-)2-butyl-1-p-tolyl-ΐΗ-π ratio Sodium) dehydro))-1-yloxy)fl is more specific than sigma-2-ylamino)-2-g-isoylethyl) oxalylamine; N-(4-(4-(3) -(3-tert-butyl-1-p-phenylene ratio π sitting _5_yl) benzyl)naphthalen-1-yloxy-carbidyl-2-yl)-2-(2-(methyl) Continuation of hydrazino) acetamido) acetamidine; N_(2-(4-(4-(3-(3-t-butyl-1- 曱 曱 基 心 心 心 心 心 心)) (naphthalene-1-yloxy) pyridin-2-ylamino)-2- ketoethyl) morphine acetophenone; N-(2-(4-(4-(3- (3-tert-butyl-1-p-toluene s_1H_nbiazole _5_yl) ureido)naphthalen-1-yloxy)pyridyl -2-ylamino)_2-ketoethyl)norfosin-4-carboxamide; N-(2-(4-(4-(3-(3-tert-butyl-1-pair) Phenyl^^^pyrazole_5_yl)ureido)n-1-yloxy)αpyrimidin-2-ylamino)_2·|isoylethyl)_2 6_ -fluoro-3-(2 -(2-decyloxyethoxy)ethoxy) azain; 201111360 N-(4-(4-(3-(3-tert-butyl-1-)-t-phenyl_ιη_π ratio σ _-(5) ureido)phenoxy)pyridin-2-yl)-2-methoxyacetamide; Ν-(4-(4-(3-(3-tert-butyl-1-) P-tolylpyrazin-5-yl)ureido)-2-methylphenoxy)acridin-2-yl)-2-methoxyacetamide; Ν-(4-(4-(3- (3-t-butyl-1-p-tolyl-iH-pyrazol-5-yl) urethyl)-3-methylphenoxy)pyridin-2-yl)-2-decyloxy Amine; Ν-(4·(4-(3·(3-tert-butyl-p-p-toluene*_ιΗ-π-biazole-5-yl))ureido)-2-methoxyphenoxy)pyridine- 2-yl)-2-decyloxyacetamidine; Ν-(4-(4-(3-(3-tert-butyl-1-p-tolyl-yl)-pyrazole-5-yl) urea -2,3-dimercaptophenoxy)acridin-2-yl)-2-decyloxyacetamidine, · Ν-(4-(4-(3-(3 tert-butyl)- 1_p-phenyl-1-indole-pyrazole-5-yl)ureido)-3-methoxyphenoxy π ratio bite_2_yl)_2_methoxyacetamide; Ν-ethyl-Ν'-4-(4-(3-(3·t-butyl-1-yl)-p-tolyl_出_ Pyrazol-5-yl)glycosyl)naphthalen-1-yloxy)-bipyridyl-2-carbazide; 4-(4-(3-(3-苐dibutyl-indole-p-tolyl-) ―. More than saliva _5_yl) uranyl) naphthalen-1-yloxy)pyridin-2-ylurea; Ν-propan-2-yl-Ν'-4-(4-(3-(3-third Butyl-1-p-phenylene-1-pyrene-1-ylide-5-yl)ureido)naphthalene-1-1-oxyl-rhenyl urea; 1-(3-(t-butyl)+(pair Stupid base) m_pyrazole-5_yl)-3-(4-((2-(3-phenylureido)))))))))) ((2-(3-Benzylureido)π-pyridyl-4-yl)oxy)naphthalenyl-(yl)-fluorene tert-butyl)-1-(p-tolyl)_1Η_0 azole-5-yl Urea; 1-(4-((2-(3-cyclopropylureido))-pyridyl-4-yl)oxy)naphthalenyl)-3-(3-(t-butyl) (p-phenylene)_m_D than spiva); 201111360 1-(3-(t-butyl)-1•(p-phenyl)_m_pyrazole-%)-3-(4-(( 2-(3-(2-decyloxy)ureido)D-pyridyl-4-yloxy)naphthalene 1-yl), ', 1-(3-(t-butyl)-1_ (p-Athyl)-pyrazole-5(yl)-3-(4-((2-(3-cyclopentyl)ureido))-pyridyl-4-yloxy) tea) Urea; τ 1-(3-(tert-butyl)_1_(p-phenyl)_m_pyrazole-5-yl)-3-(4-((2-(3-indolyl)))) _4_yl)oxy)teaine base) intestine; 2-(3-(4-(4-(3-(3-(3rd) Small (p-phenylene)_m_n-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)ureido)ethyl acetate; 4-(3-(4-( 4-(3-(3-tert-butyl-indole-p-tolyl·m_pyrazole-5-yl) ureido)naphthalen-1-yloxy)acridin-2-yl)ureido) Hydrogen pyridine; Ν-acetamido 4-(3-(4-(4-(3-(3-tert-butyl)-p-p-benzobenzene*_1Η-pyrazol-5-yl)ureido) naphthalene- I-yloxy)acridine_2-yl)ureido)hexahydropyridine; 2-(2-decyloxyethoxy)_ι_(4_(3_(4·(4-(3-(3-) Tributyl _ι_ p-methyl phenyl-1 Η-吼. succinyl) ureido) naphthalene small oxy) oxime ratio 0 _2 _ _ ureido) hexahydropyridin-1-yl) ethyl ketone; - 曱 continuation g basket-4-(3-(4-(4-(3-(3-tert-butyl-1-)-p-tolyl-1Η-η than salinyl))))) ))pyridinyl-2-yl)ureido)hexahydropyridine; Ν-(4-(4-(3-(3-tert-butyl-1- 1-p-tolyl_丨Η_π-pyrazole-5-yl) Glycosyl)naphthalenyloxy)D-pyridin-2-yl)morpholine-4-carboxamide; 42 201111360 N-(4-(3-(3-(3-(t-butyl) )-1-(p-tolyl)-1Η-η-biazole-5-yl)-yl)tea-1-yl)lacyl)π-biti-2-yl)-4-mercaptohexanitrogen 17 to ^ -1-^ guanamine; 3-(4-((4- (3-(3-(Tert-butyl)-1-(p-phenylene)-1Η-α-pyrazol-5-yl)urea)Nylidene-1-yl))) -yl)-1,1-dimercaptoyl, Ν-(4-((4-(3-(3-(t-butyl))-1-(p-tolyl)-1 - oxazole-5-) )))))))) 蒸 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 甲基 甲基 甲基 甲基 甲基 甲基 甲基4-yl)ethyl)-indole-4-(4-(3-(3-tert-butyl-1-p-phenylene-1Η-αι^σ sitting-5-yl))) 1-based lactyl)ntb^ -2 - base pulse, N-(4-(morpholine-4-yl)butyl-: ΝΤ-4-(4-(3-(3-tert-butyl-) 1-p-phenylene-1Η-Π is 0--5-based) uranyl)N--1-yloxy)0 〇定定-2_基月尿, Ν-(2-(?福咁4-yl)ethyl)-Ν'-4-(4-(3-(3-t-butyl-1-p-phenyl)-pyridin-5-yl)ureido)-naphthalene-1 -yloxy)acridin-2-ylurea; Ν-(3-methylisoxazol-5-yl)indolyl-^-4-(4-(3-(3-tert-butyl-1) -p-tolyl-1 oxime-oxazol-5-yl)ureido)naphthalen-1-yloxybutyryl-2-ylurea; N-(1-methyl)hexahydropyridin-4-yl-oxime '-4-(4-(3-(3-tert-butyl-1-p-tolyl-1Η- ° ratio α--5-yl)) ketone)-n-yl-based)atb定-2-ylurea; N-(4-(4-(3-(3-tert-butyl-1-p-phenylene-1H-carbazol-5-yl))) -yloxy) 11 is more than decyl-2-yl)-4-ylpyrrolidine ° ° -1 - slow-acting amine;

43 S 201111360 N-(3-( 口米π坐-1 -yl)propyl)-1^-4-(4-(3-(3-di-dibutyl-1 -p-phenylene-1Η-) Pyrazol-5-yl)ureido)naphthyl-buyloxy)pyridin-2-ylurea; Ν-(2-(3-(4<4_(3-(3-tert-butyl-1-) Tolyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)ureido)ethinyl)tetrahydropyrrole; (r)_N-(4-( 4-(3-(3-Tertibutyl-1_p-phenylene-1Η-indazol-5-yl)ureido)naphthalen-1-yloxy)°pyridin-2-yl)-3 -(didecylamino)tetrahydrofuran-1-carboxamide; N-(4-(4-(3-(3-tert-butyl-1-p-phenylene-1H-pyrazole)- 5-yl) ureido)naphthalen-1-yloxy)pyridin-2-yl)tetrahydropyrrole-1-carboxyguanamine; 2-(3-(4-(4-(3-(3-) Butyl-1-p-phenyl-lH-α-biazole-5-yl)ureido)naphthalen-1-yloxy)D-pyridin-2-yl)ureido)-indole-methylacetamide ; 2-(3-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1Η-indazol-5-yl))))) Bis-2-yl)ureido)-indole-(2-morpholinoethyl) acetamidine; 2-(3-(4-(4-(3-(3-tert-butyl-1) -p-tolyl-1Η-indazol-5-yl)ureido)naphthalen-1-yloxy)α-pyridin-2-yl)ureido)ethinyloxaporphyrin; 2-(3-(4 - (4-(3-(3-tert-butyl-1-p-tolyl-lH-αbiazole-5-yl))ureido)naphthalen-1-yloxy)°biti-2-yl)urea ()-Ν-(2-pyridin-4-yl)ethyl)acetamide; Ν-(3-(1Η-imidazol-1-yl)propyl)-2-(3-(4-(4) -(3-(3-tert-butyl-1-p-phenylene-1Η-indazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)ureido) Guanamine; 44 201111360 1-(2-(3-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-indazol-5-yl))) -1-yloxy)-pyridin-2-yl)ureido)ethinyl)-4-methylhexahydro- 0-pyridyl; Ν-(3-(1Η-imidazol-1-yl)propyl )-2-(3-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1Η-.bazol-5-yl)))-naphthalen-1-yloxy (Acridine-2-yl)ureido)acetamide; Ν-(6-(4-(3-(3-tert-butyl-1-p-tolyl-1Η-pyrazol-5-yl)) Urea-based) Qin-1-yloxy) acetophenone-4-yl)-2-decyloxyacetic acid amine, Ν-(6-(4-(3-(3-tert-butyl-1-)曱Phenyl-1Η-«bazin-5-yl)ureido)phenoxy)pyrimidin-4-yl)-2-oxoethoxyacetamide; Ν-(4-(4-(3-(3) -T-butyl-1-p-phenylene-lH-η-biazole-5-yl) urethral) tea-1-yl lactyl)^σ-but-2-yl)-2-methoxy B Amine, 3-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1Η-indazol-5-yl)ureido)naphthalen-1-yloxy)pyrimidine-2 -yl)urea; 1-methyl-3-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1-indole-5-yl))- 1-based lactyl)β-denyridin-2-yl), 1,1-dimercapto-3-(4-(4-(3-(3-tert-butyl-1-p-phenyl)phenyl) -1Η-. Biazo-5-yl)ureido)naphthalen-1-yloxypyrimidin-2-yl)urea; 1-cyclopropyl-3-(4-(4-(3-(3-tert-butyl) -1-p-tolyl-1Η-pyridinium-5-yl)|uronyl)na-1-yloxy)π_π·^-2-yl) monthly urine, (4-(4-(3-( 3-tert-butyl-1-p-phenylene-1Η-oxazol-5-yl)ureido)-hhenyl-1-yloxy-denyl 11-but-2-yl)fosino-4-acid acid amine , 3-(6-(4-(3-(3-Tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyrimidine-4 -base) urea;

45 S 201111360

L η is more than saliva or its medicinal tautomers and

/ soil, factory pupils to sign makeup 'Dan has the following formula:

Or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers and tautomers thereof. Examples of the compound (I) salt include all pharmaceutically acceptable salts, without limitation, such as acid addition salts of strong inorganic acids such as HCl and HBr salts and addition salts of strong organic acids such as methyl sulphonate. Unless otherwise specified in the text, the definition of a compound of the formula (1) as used herein is intended to include salts, solvates, and all tautomers of the compound. Examples of solvates include hydrates. As used herein, the invention provides a compound of formula (I) which is extended to a prodrug of a compound of formula (I), i.e., a compound which cleaves and/or metabolizes in vivo to provide activity. General examples of prodrugs include simple esters and other esters such as mixed tartrates, amino phthalates, glycosides, ethers, chains and ketones. 46 201111360 Another aspect of the invention provides a metabolite of one or more compounds of formula (i), particularly a metabolite that retains the therapeutic activity of one or more compounds of formula (I). The metabolites used herein are compounds produced by metabolism of a compound of formula (I) in vivo, without limitation, such as oxidative metabolites and/or metabolites formed, such as from 0-desane. Base role. Compounds of the present disclosure include those in which a particular atom is naturally or non-naturally produced. In one embodiment, the isotope is a stable isotope. Accordingly, the compounds of the present disclosure include, for example, an organic compound or the like. The compounds described herein may include one or more pairs of palm centers, and the disclosure broadly includes the racemates, enantiomers, and stereoisomers produced therefrom. In one embodiment, one enantiomeric version is presented in a substantially pure form which is substantially free of related enantiomers. The disclosure also extends to all polymorphic forms of the compounds defined herein. Unless otherwise indicated in the text, other references to compounds of formula (I) herein include reference to one or more of the structures and compounds as disclosed. The compound of formula (I) can be included by including a compound of formula (II):

47 S 201111360 R1

Wherein, Ar, X, Rl, R2 and R3 are as defined in the compound of the above formula (I), wherein Q is not -NHR* (wherein R* is the remainder of the Q fragment) and the compound of the formula (Ilia): 〇

(INa) wherein LGI is prepared by reacting a cleavage group such as a halogen such as chlorine. When NR3C(0)Q is NR3C(0)NHR*, the compound of formula (I) can be prepared by reacting a compound of formula (II) with a compound of formula (Illb): Q = C = Ο (mb). This reaction is suitably carried out in the presence of a base such as DIPEA. The reaction is suitably carried out in an aprotic solvent or solvent mixture such as DCM and DMF. The compound of formula (II) can be obtained by the compound of formula (IV): 48 201111360 R1

NH2 (IV) wherein R1 and R2 are as defined in the compound of the above formula (1), and formula (VI)

Compound: wherein LG2 and LG3 each independently represent a release group (for example, LG2 is CI3CO- and LG3 is C1. Or both LG2 and LG3 may be the same, for example, LG2 and LG3 both represent an imidazolyl group or a halogen such as chlorine) The reaction is carried out, followed by preparation of a reaction of the formula (V):, Ar-X.H2N〆, NHR3 wherein Ar, X and R3 are as defined in the compound of the above formula (I). This reaction is suitably carried out in an aprotic solvent (e.g., dichloromethane) using a protecting group of a suitable chemically sensitive group and a base such as DIPEA. Specifically, a compound of formula (II) can be obtained by formulating a compound of formula (IVa):

S 49 201111360 R1

(IVa) wherein R1 and R2 are as defined in the compound of the above formula (I), and are reacted with the compound of the formula (v). The reaction can be carried out in the presence of a steric hindrance such as DIPEA in a suitable inert solvent such as dichloromethane. Compounds of formula (I) wherein R2 is a carbyl group can be prepared, for example, by reacting a sulfonyl phenyl acid with a decyl acetonitrile such as R1C(0)CH2CN. The coupling interaction can be effected in the presence of an alcohol solvent such as ethanol and a mineral acid such as HCl, followed by treatment with lithium hydroxide in a solvent such as THF. The substituent r2 comprising a hydroxyalkyl group can be represented by reduction using borax-containing in a suitable solvent such as THF to give a compound of the formula (IV) wherein R2 is a hydroxylated alkyl group. The 29 group can then be protected, for example, as a decane ether and (IV) can be formed via one of the routes illustrated in this section to form a compound of formula (1) wherein r2 is a protected hydroxyalkyl group. The hydroxyl group can be revealed by cleavage of a cerium alkyl group (siUyl) group, for example, with tetrabutylammonium fluoride. A compound of formula (I) wherein R1 is a hydroxylated alkyl group can be reacted by using a benzyloxyalkyl decyl acetonitrile and an aryl group similar to those described directly above. preparation. 50 201111360 Compounds of formula (IVa) can be prepared by reacting a compound of formula (IV) with phosgene or phosgene equivalents such as diphosgene or triphosgene in the presence of a base such as DIPEA. It is understood by those of ordinary skill in the art that the compound of formula (IVa) is generally a reactive intermediate and can be isolated and used directly in subsequent conversion or can be a temporary intermediate which is in situ. It is produced and does not need to be used separately. More specifically, a compound of formula (II) can be obtained by formulating a compound of formula (IVb):

R1 (IVb) wherein 'LG2 is defined as previously prepared by reacting a compound of formula (VI). The reaction can be carried out in the presence of a sterically hindered base such as DIPEA in a suitable inert solvent such as dichlorohydrazine. The compound of the formula (IVb) can be produced by reacting a compound of the formula (IV) with a compound of the formula (VI) in the presence of a base such as DIPEA. Those having ordinary knowledge in the art should understand that the compound of the formula (Ivb) can be intermediate Body, including transient intermediates that have not been isolated. The compound of the formula (V) can be obtained by the compound of the formula (VII): 〇2N/Ar, 〇/X, NHR3 (VII)

S 51 201111360 : Second, 'Ar·' X&r3 is defined as being reduced in the compound of the above formula (1), for example by hydrogenation in the presence of a catalyst such as flaky charcoal. The reaction is suitably carried out in a polar aprotic solvent or solvent mixture (10) decyl alcohol and acetic acid). Alternatively, the compound of formula (v) can be obtained by formulating a compound of formula (vma):

At y p1p2n〆, 〇〆, R3p3 (Vila) ==crR:, r is defined as before (1) to protect. 20乙醯基)) TM20TM3 Formula (νπ) compound can be defined by the formula (vm) compound, H〇~X-NHR3' (VIII) and R3' is as defined above, where 'X is defined as In the compound of the formula (1) (Vila): Compound of the formula (IX) or (X): o2n h (X) (IX) "Prepared by reacting R as a halogen such as fluorine. Compound (10)) and (X) It can be defined as any substituent in the compound of the above formula (1). In the case of 52 201111360, in the example, 'the operation and the chat with the money are opposite to those of the others. Yu Qiangru

In the presence of the "non-temporary non-temporary work", U, & is for the child's health, such as. In an alternative method, a specific compound of the formula (V) wherein Ar and X - are as defined in the compound of the above formula (I), can be obtained by a compound of the formula (χι): 疋 Η, ". ', (XI) or ^ protective derivative, such as the amine group A (four), wherein Α ^ χ defined as such and LG4 represents a release group such as chlorine (especially for X represents (four)) and amelting agent, for example with Urethane (XII): 0

X rLn'^p3 η (XU) Ρ and R3 如 are as prepared in the presence of an anhydrous inert solvent such as THF, appropriate 16 catalysts, for example, under nitrogen pressure, and then the original and new Both amines are protected, for example by using a gas-burning and TFA to protect.

In one embodiment, the compound of formula (XII) is R3HN^〇tBu or (Xlla) (Xllb). The compound of formula (XI) can be obtained by formulating compound (XIII) h2n〆, OH (XIII) s 53 201111360 or Its protective derivative 'for example when the free amine is protected as an amino decanoate, wherein Ar is as defined above with the compound of formula (XIV): LG^ LG4 (XIV) wherein X is as defined above and LG4 represents a cleavage group such as chlorine And LG5 represents a release of a base such as fluorine to make a bond. The reaction can be carried out in the presence of a strong test such as sodium hydride in a polar aprotic solvent such as DMF. The reaction can be carried out in an inert solvent in the presence of a catalyst such as Pd. In one embodiment, the compound of formula (XIV) is:

F

N〆 'CI

And with formula (XV) or (XVI) compound HO

H2N

(XV)

HO h2n (XVI) performs the reaction. In the presence of butanol unreacting, the reaction may be carried out in a strong test such as a second protic solvent such as NMP or the compound of formula (I) may be obtained by a compound of formula (XVII): 54 201111360

Wherein Ar, X, R3 and Q are as defined in the compound of the above formula (I), and the compound of the formula (XVIII):

Wherein R1 and R2 are as defined in the compound of the above formula (I) and LG7 is reacted as a release group. The reaction can be carried out in an aprotic solvent such as DCM at room temperature. Particular compounds of formula (I), for example compounds wherein Q represents C!_6 alkyl NH2, can be converted to other compounds of formula (I) by reaction with a oximation agent. a compound of formula (I) wherein Q is bonded to -NR3C(0) by -CH2V, wherein V is a hetero atom selected from ruthenium, osmium, or S, by means of a method comprising a nucleophilic displacement reaction On the compound (Ila):

55 S 201111360 wherein R1, R2, x and R3 are as defined in the compound of the above formula (I) and LG6 represents a cleavage group such as a halogen such as chlorine and a compound of the formula (χιχ): Η — V′ — q(xix) wherein Η represents hydrogen, ν represents a hetero atom selected from ruthenium, osmium, iridium, or 8 and q represents a residual portion of Q (ie, _CH2V, _q; = (7) is prepared. The reaction can be sterically hindered The base, for example in the presence of DIPEA, is carried out in an inert solvent such as a two-gas methane. The compound (IIa) can be combined with the formula (XX) by the compound of formula (II).

Wherein LG6 is as defined in the compound of the above formula (Ila), and LG7 is prepared as a cleavage group such as a halogen such as gas. The lower portion is carried out in an inert solvent such as methylene chloride. The reaction can be carried out, for example, in a sterically hindered base such as dIPEA from a compound of ^(1) wherein Q is NH-(CH2)d-C(〇)NHRd, by means of inclusion (called:

56 201111360 wherein R1, R2, Ar, X and R3 are as defined in the compound of the above formula (1) and d is an integer from 1 to 5 (eg 1 to 4), and a coupling agent such as EDC is used with the amine RdNH2 (where Rd represents Q) Prepared by a fragment). The compound of the formula (Hb) can be synthesized by reacting the compound (9) with a hypomorphic acid ester of the formula (IIIb) wherein Q is N-(CH2)dC〇2Et, and then the resulting ethyl ester product is used, for example, The aqueous lithium hydroxide is hydrolyzed in THF. A compound of formula (I) wherein Q is NR4R5 may be included between the amine R4R5NH and the compound of formula (He): R1

Wherein 'Rl, r2' Ar, x and R3 are as defined in the compound of the above formula (I) and LG2 is a method in which a cleavage group such as 2-isopropenyloxy is reacted. The compound of the formula (IIc) can be synthesized by reacting a compound of the formula (II) with a compound of the formula (VI), such as isopropenyl phthalate, in the presence of a hindered base such as DIPEA. The reaction can be carried out in the presence of a sterically hindered base such as DIPEA in an inert solvent such as dichloromethane. The specific compound of the formula (I) wherein Ar is a napthyl group and the oxime is a bite group is prepared in the following schemes. Process 1

S 57 201111360

Wherein R1 and R2 are as defined in the compound of the above formula (I). Scheme 2 outlines the route of preparation of a particular compound of formula (I). Process 2 58 201111360

Intermediate A

Amide Examples

Intermediate B

Urea Coupling

Amide Coupling

Wherein R1 and R2 are as defined in the compound of the above formula (I). Compounds of formula (I) wherein XNR3(CO)Q represents N-fluorenyl-2-aminopyrimidinyl or N-fluorenyl-4-aminopyrimidinyl can be prepared as outlined in Scheme 3 below: Scheme 3

Intermediate I

OR Intermediate C

Wherein, each of X' and Y' independently represents CH or N. 59 201111360

A compound of formula (I) wherein Ar represents a naphthyl group and XNR3c(〇)Q represents an N-decyl-2-aminopyrimidinyl group can be prepared as outlined in Scheme 4 below: Scheme 4

Where 'X' and Y' independently represent CH or N. Compounds of formula (I) wherein XNHR3 represents 2-aminopyrimidinyl or 4-aminopyrimidinyl and NR3(CO)Q is urea can be prepared as outlined in Scheme 5 below: Scheme 5

Wherein, X' and Y' independently represent CH or N. 201111360 The following Scheme 6 is a summary of other compounds of formula (I) wherein Ar is naphthyl and XNHR3 represents 2-aminopyrimidinyl or 4-aminopyrimidinyl: Scheme 6

The starting material for the preparation of 4-aminopyrimidines in Scheme 6 can be as outlined in Scheme 7:

Or prepared as shown in Process 8:

OH

Base 61 201111360 Specific compounds within the definition of intermediate Μ*, especially intermediate Ν, where XNHR3 is 2-aminopyrimidinyl and L is oxime, can be prepared as shown in Scheme 9: Scheme 9

Intermediate N < Intermediate K wherein Q is NRR' can be prepared as outlined in Scheme 10 below: 62 201111360

Here, each of X', R and R' is as defined above. An example of the route of the compound of Example 8, which is a specific example of the compound of formula (1), is shown in Schemes 11 and 12 below. Scheme 11 is similar to Scheme 1 except that it is related to the specific compound of Example 8. Process 11

63 S 201111360

Scheme 12 illustrates that the compound 8 is reacted by the compound (1) in the presence of a compound of the formula (XVII) and a compound (g) in the presence of a coupling agent of the formula (VI), in this case 1,1- An example of a route for the preparation of carbonyldiimidazole (CDI). This method is similar to Scheme 2, in which compound (1) of Scheme 12 corresponds to Intermediate C of Scheme 2 and Compound (g) of Scheme 12 corresponds to Intermediate B of Scheme 2. Process 12 64 201111360

OH

Formula (III), (IV), (IVa), (IVb), (VI), (VIII), (IX) '(X) '(XII), (Xlla), (Xllb), (XIV), ( Compounds of XV), (XVI), (XIX) and (XX) and starting materials for the reaction scheme are commercially available, either known or novel and can be readily prepared by conventional methods. See, for example, Reagan, J., et al; Journal of Medicinal Chemistry, 2003, 46, 4676-4686, WO00/043384, WO2007/087448, and W02007/089512. When one or more of the above reactions are carried out, a protecting group may be required to protect the chemically sensitive group to determine that the method is effective. Thus, intermediate compounds can be protected by the use of customary protecting groups if desired or desired. The protective groups and the tools used to remove them are described in the "Protective Groups in Organic Synthesis" by Iodora W. Gliny and G.M. Woods.

S 65 201111360 John Wiley & Sons is published in 0471697540. 4th edition, 2006, ISBN-10: The novel intermediate system is the aspect of the application for the invention. Formula (I) & is a p38 map agglutination inhibitor and in one aspect the compound is used to treat a disease, such as c〇pD and/or asthma. It is known that the p38 MAP kinase inhibitor, such as birb796, appears to have a long duration of action and/or persistence of action. In the case of the individual, the compound of formula (1) is a (iv) MAPKa and/or gamma subtype inhibitor. Retranslatability herein relates to the dissociation rate or dissociation constant of a compound in a subject (e.g., a receptor). A low dissociation rate can result in persistence. The low dissociation rate has a tendency to provide an effective therapeutic essence when combined. The compound of formula (I) has potency in the living body. In one aspect, the compound is used to treat, for example, c〇pD. and/or asthma. The development of this compound has so far been intended to be usually administered orally. This goal includes the optimization of the pharmacokinetics of W to achieve the optimization of its duration of action. This is believed to establish sufficient drug concentration and thereafter The clinical benefit is provided by maintaining the dose. The inevitable result of this treatment is that all body tissues, especially (10), will also be exposed to the active concentration of the drug, whether or not it is Negative impact. 66 201111360 The alternative strategy is to design a direct administration of the drug to the inflammatory regimen (localized strip). However, this treatment is not suitable for all chronic inflammatory diseases. It has been widely used in lung diseases (asthma, ' COPD) 'dermatological diseases (atopic dermatitis and psoriasis), nasal diseases (di-sensitive rhinitis) and gastrointestinal diseases (ulcerative colitis). During treatment, the risk of systemic toxicity can be minimized by (1) convinced that the drug has a sustained use period and remains in the relevant organ or (ii) that the production will produce a drug benefit for continued use. The reservoir is formulated to achieve efficacy. The method (i) can be exemplified by the anti-cholinergic drug ti〇tr〇piUm (Berlinga, SpiHva), which is administered topically to the lungs. Dealing with c〇PD, and having an abnormally ambiguous affinity in the style of the second two, resulting in a very slow off rate and an inevitable sustained period of action. The compounds of formula (I) are particularly suitable for topical delivery, such as topical delivery to the lungs, particularly for the treatment of respiratory diseases, such as chronic respiratory diseases such as C〇PD and/or asthma. In our example, the compound of formula (1) It is suitable for sensitive patients who have been treated with corticosteroids and whose treatment has become ruminant. The compound of formula (1) can also be used to treat rheumatoid arthritis. The compound of formula (1) can have antiviral properties, for example Avoid cell infections with tiny RN A viruses (eg Withdrawing ability of epithelial cells), particularly rhinovirus, respiratory flow essays m stomach or viruses.

S 67 201111360 Therefore, the compound is considered to be an antiviral agent and is particularly useful for avoiding, treating or ameliorating microRNA infections such as rhinovirus infections, influenza or respiratory viruses. In one embodiment, the compound of formula (I) is capable of reducing inflammation induced by viral infection, such as rhinovirus infection and particularly by viral infection of cytokines such as IL-8, especially in vivo. This activity can be tested, for example, in vitro using an IL-8 assay induced by rhinovirus as illustrated in the Examples herein. In one embodiment, the compound of formula (I) is capable of reducing the expression of ICAM1 induced by rhinoviruses, particularly in vivo. ICAM1 is a receptor mechanism used to infect cells by the so-called major maj or groove rhinovirus serotype. This activity can be used, for example, as determined by the methods illustrated in the Examples herein. It is to be expected that the above-mentioned properties motivate the compounds of formula (I) to be particularly suitable for the treatment and/or prophylaxis of patients having one or more of the following chronic conditions such as heart failure, COPD, asthma, diabetes, cancer and/or For example, the deterioration of immune suppression in patients after organ transplantation, especially the deterioration of the virus. In particular, the compound of formula (I) can be used to treat one or more respiratory disorders including COPD (including chronic bronchitis and emphysema), asthma, pediatric asthma, cystic fibrosis, sarcoidosis, primary pulmonary fibrosis, Allergic rhinitis, rhinitis, sinusitis, especially asthma and COPD (including chronic bronchitis and emphysema). 68 201111360 Compounds of formula (i) may also be used to treat one or more symptoms that may be treated by topical or local treatment, including allergic membranous inflammation, conjunctivitis, allergic dermatitis, contact with dermatitis, Psoriasis is produced, colitis of the colitis, rheumatoid arthritis or osteoarthritis = inflammation. It is also expected that the compound of formula (1) can be used to treat other specific diseases including rheumatoid arthritis, pancreatitis, disease, tumor suppression: non-small cell lung cancer, breast cancer, stomach cancer, colorectal cancer and malignant melanoma. Growth and transfer. Tian (I), in the case of the symptoms of the patient to the same treatment, can also make the patient's symptoms and sensitization and use cortex:: - In the case of 'the compound has a longer length than the surface 796', the present invention provides a pharmaceutical group, not =: body = intentional 舆 - species or more _ = bureau 2: = those applicable - ^ Μ For example, if the above-mentioned households are mentioned, such compositions can be administered, for example, parenterally, subcutaneously, intramuscularly, intravenously, intra-articularly, or in a single (four) cut-to-injection, especially in the form of =: 2: =; when administered orally, _ is for the end of the "f; ° 4, for example, when administered intrapulmonarily or intranasally, especially for the type of private, nasal drops or aerosols and transdermal administration;

S 69 201111360 And when the anus is administered to the cavity, sublingual or vaginal mucosa, for example, in the form of a suppository, the substance can be used by the heart: =::==一雷明二: The state is called (ms) in the city of St., Pennsylvania, sterile water or salt water, stretched ethylene glycol such as C, alcohol such as polyethylene glycol, natural vegetable oil, diterpene, ί. When the formula is given, the formulation may be solid and may contain sucrose or dextran, or may be used in the form of a nasal or metered spray for aqueous or oily solutions. For oral administration, blood type excipients include sugars, stearic acid, magnesium stearate, pregelatinized powders, and the like. Compositions suitable for sputum administration may include one or more physiologically compatible carriers and/or the form may be in solid or liquid form. Sharpeners and private capsules can be used as binders, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol Or glycine; a lubricant such as magnesium stearate, talc, polyethylene glycol, or vermiculite; and a surfactant such as sodium lauryl sulfate. The liquid composition may contain conventional additives such as suspending agents such as sorbitol syrup, decyl cellulose, syrup, gelatin, carboxymethyl-cellulose, or edible fat; emulsifiers such as lecithin, or acacia; Vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxy 201111360 benzoquinone HA) and butylated hydrazine (Bht). The liquid composition can be formulated, for example, by encapsulating gelatin in a single dosage form. Solid oral dosage forms include blistering agents, two-plate hard capsules, and soft elastic gelatin (SEG) capsules. • Dry shell formulations typically comprise from about 40% to about 6% by weight of the gelatin produced in the country, from about 20% to about 30% by weight of the forming agent (e.g., gansu, oxalate or propylene glycol) and about 3G. /. Water to 40% concentration. Other substances such as preservatives, dyes, sunscreens and additions (4) may also be present. (4) The filling substance contains a solid drug or a carrier compound such as mineral oil, vegetable oil or triglyceride which has been dissolved, liquefied or dispersed (with a suspending agent such as beeswax, hydrogenated oil or polyethylene glycol 4_). , liquid medicine in ethylene glycol, polyhydric alcohol and surface-active agent. Suitably the compound of formula (I) is administered topically to the lungs. Accordingly, the present invention provides a pharmaceutical composition according to the present invention comprising the & aliquot of the present disclosure optionally combined with one or more topically acceptable diluents or carriers. Topical administration to the lungs can be achieved by using an aerosol formulation. Aerosol formulations typically comprise an active ingredient suspended or dissolved in an appropriate aerosol propellant, such as a gas fluorocarbon (CFC) or hydrogen carbon (HFC). Suitable CFC propellants include tri-gas-fluoromethane (propellant u), di-gas tetrafluoromethane (propellant 114), and di-hydro-difluoromethane (propellant). Suitable HFC propellants include tetrafluoroethylene (HFC_134a) and sevoflurane (HFC-227). The propellant typically comprises from 40% to 99.5%, for example from 40% to 90% by weight of the total inhalation composition. The formulation may include 3 excipients with auxiliary granules (e.g., ethanol) and surfactants (e.g., 纟P fat, £71 201111360 sorbitan trioleate, etc.). The aerosol formulation is packaged in a canister and the appropriate dose is delivered by a metering valve (e.g., supplied by Bespak 'Valois or 3M). Topical administration to the lungs can also be achieved by the use of non-pressurizing formulations such as aqueous solutions or suspensions. This can be administered with a nebulizer. Topical administration to the lungs can also be achieved using a dry-powder formulation. Dry powder formulations typically contain an extremely dispersed form of the intrinsic granules of an average particle size of 1-10 microns mass (MMAD). The formulation typically contains 'partially acceptable diluents such as lactose, often those having a large particle size such as a mass average particle size (MMAD) of 100 microns or greater. Examples of dry powder delivery systems include rotary powder inhaler (SPINHALER), dish dry powder inhaler (DISKHALER), multi-dose quantitative dry powder inhaler (TURBOHALER) 'cake dry powder inhalation||(DIsKUS) and point-type dry powder inhalation (CLICKHALER). The compound of formula (1) has therapeutic activity. In another aspect, the invention provides a compound of formula (I) for use as a pharmaceutical. Thus, in another aspect, the invention provides a compound as described herein for the treatment of one or more of the above mentioned conditions. In another aspect, the invention relates to the use of a compound as described herein for the manufacture of a medicament for treating one or more of the above mentioned conditions. 72 201111360 In another aspect, the invention provides a method of treating one or more of the above mentioned conditions, which comprises administering to an individual an effective amount of a compound of the present disclosure or a pharmaceutical composition comprising the compound. The term ''treatment' is intended to cover both prophylactic and therapeutic treatment. The compounds of the present disclosure may also be administered in combination with one or more other active ingredients, for example, active ingredients suitable for treating the above conditions. For example, for treating respiratory disorders. Possible compositions include steroid-containing compositions (e.g., budesonide, beclomethasone dipropionate, fluticasone), and guantan decanoate ( Mometasone furoate), fluticasone furoate 'β agonist (eg terbutaline, salbutamol, salmeterol, formoterol) And/or jaundice (eg tea test). Other suitable actives include anticholinergics, such as tiotropium and anti-viral agents, but not limited to mulberry (zanamivir) or oseltamivir, such as sulphate. Other anti-viral agents include peramivir and laninamivir. The following formula (I) Data relating to antiviral properties of the compounds convince the inventors that other antiviral therapies are useful for treating or preventing the progression of patients with respiratory diseases such as COPD and/or asthma and/or one or more of the indications listed above. Therefore, in one aspect, an anti-viral treatment such as, but not limited to, zanamavir or oseltamivir (such as oseltamivir sulphate) is provided.

73 S 201111360 Use in the treatment of respiratory viremia infection in patients with chronic conditions such as congestive heart failure, diabetes, cancer, or in immunosuppressed patients such as organ transplantation. Abbreviations Any abbreviations not used herein are defined as the abbreviations AcOH Aq Ac as defined in the following table. These are generally accepted as the yoke glacial acetic acid ~ water-based ethyl alcohol ATP BALF 9-BBN Boc br BSA CatCart® CBz CDI COPD D Pd2(dba)3 DCM DIAD DIBAL-H DMAP DIPEA DMF DMSO ELISA EDC.HC1 adenosine-5'-tribasic acid lung extract 9-borobicyclo[3.3.1]decane third butoxide Carbocarbonyl broad-area bovine serum albumin catalyzes the ruthenium-based gas group, l-l-group-dimi-jun chronic obstructive pulmonary disease bimodal bis(monooctylacetone) di-I-bar methylene chloride-iso-diyl Aza-dioxalate oxime-isobutyl hydride N,N-dimercaptopyridine_4_amine N,N-diisopropylethylamine N, dimethyl carbamide Immunosorbent assay by enzyme-linked immunosorbent assay for 1-ethyl-3-(3-didecylaminopropyl)carbodiimide. Hydrogenation 74

201111360 (ES+) Et EtOAc FCS FRET HEPES

HOBt hr HRP HRV ICAM1 IgG IL-8 KHMDS LPS (M+H)+ MAPK MAPKAP-K2

Me MeOH MHz min MOM-Br MTT m/z :

NSE OD electrospray ionization, positive mode ethyl acetate, fetal calf, jk clear fluorescence, resonance energy transfer, 2-(4-(2-hydroxyethyl)hexahydropyrazine-1 -yl)ethanesulfonic acid 1 -Hydroxybenzotriazole Hourly Horseradish Peroxidase Human Rhinovirus Intercellular Adhesion Molecule 1 Immunoglobulin Leukocyte Interleunin 8 c-Jun N-Terminal Kinase Hexamethyldiamine-N-potassium-potassium Polysaccharide Protonated Molecular Metabolic protein-activated protein kinase via rice mitre-activated protein kinase-activated protein kinase 2 thiol methanol megahertz-minute bromodecyl oxime 3-(4,5-dimercaptothiazol-2-yl)- 2,5-diphenyltetrazole impurity mass-charge rate N-fluorenyl hydrazide; (4-methylmorpholine) 1-mercaptotetrahydropyridin-2-one (N-曱Base-2-σ ratio 17 ketones) Nuclear magnetic resonance (spectrophotometer) No significant effect optical density

75 S 201111360 PBMC End of the blood mononuclear Ph Ph PBS PBS phosphate buffered saline PMA croton peas vinegar vinegar wrong acid 酉 Pd2 (dba) 3 tris(dibenzylideneacetone) dipalladium (〇) PPh3 Triphenylphosphine PyBOP® (benzotrisyl-1-yloxy)tritetrahydroanthracene sulphate hexafluoroantate RT quadruple peak room temperature RSV respiratory virus RPHPLC reverse phase effect liquid chromatography s unimodal " sex solid support cation exchanger (resin) SDS sodium lauryl sulfate Si〇2 tannin t three peak TCID5 〇 50% tissue culture infectious dose TFA trifluoroacetic acid THF tetrahydroanthracene 0 south TMB 3,3 ·,5,5·-tetradecylbenzidine TNFa tumor necrosis factor alpha TMS-C1 tridecylsulfonyl vapor hydride [gas triterpene oxime x XantPhos 4,5_bis (a phosphinyl)- 9,9-Dimercaptooxaxene General Procedures All starting materials and solvents are obtained from commercial sources or prepared according to the literature. The hydrogenation was carried out on a Thales H-cube flow reactor under the conditions indicated. The organic solution is customarily dried over magnesium sulfate. 76 201111360 SCX is commercially available from Supper and is treated with 1 M hydrochloric acid prior to use. Unless otherwise stated, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. The solution was loaded directly onto SCX and washed with MeOH. The desired material was then eluted by washing with 1% NH3 in MeOH. Column chromatography is performed on pre-filled vermiculite (230-400 mesh '40-63 μΜ) using the indicated quantities. Preparative reverse phase high performance liquid chromatography: Agilent Scalar column C18, 5 micron (21.2 x 50 mm), flow rate 28 ml. min-1 with oi% volume/volume formic acid The H2〇-MeCN gradient was eluted during 1 min using UV detection at 215 and 254 nm. Gradient data: 〇.〇_ 0.5 min: 95% H2〇-5% MeCN; 0.5 -7.0 min; ramped from 95% H2〇-5% MeCN to 5% H20-95% MeCN; 7.0 -7.9 min : 5% in H2〇-95% MeCN; 7.9 -8.0 minutes··return to 95% H2〇-5% MeCN; 8.0-10.0 minutes: lasts in 95% H2〇-5% MeCN. Analytical method Reverse phase effect liquid chromatography: Agilent Scala column C18, 5 micron (4.6 x 50 mm) or Waters XBridge C18, 5 micron (4.6 x 50 mm) flow rate 2.5 ml Minute-1 was eluted with a H20-MeCN gradient containing 〇·ι% by volume/volume of citric acid over 7 minutes using UV at 215 and 254 nm. Gradient data: 〇.〇—(U minutes: 95% 77 201111360 H2〇-5% MeCN; 0.1-5.0 minutes; from 95% H2〇-5% MeCN to 5% H2〇-95% MeCN; 5.0 -5.5 Minutes: lasts 5% H2〇-95% MeCN; 5.5-5.6 minutes: lasts 5% H2〇-95% MeCN, flow rate increases to 3.5 ml. min-1; 5.6 -6.6 min: lasts 5% H2〇-95%MeCN, flow rate 3.5 ml.min-1; 6.6 -6.75 min: return to 95% H2〇-5% MeCN, flow rate 3.5 ml.min-1; 6.75-6.9 min: lasts 95% Η2 〇·5% MeCN, flow rate 3.5 ml. min-1; 6.9-7.0 min: lasting 95% H2〇-5% MeCN, flow rate reduced to 2.5 ml. min-1. 1H NMR spectrometry: Bruck Afans III 400 MHz uses a residual unvaporized solvent as a reference. Specific compounds of the present disclosure are prepared by a method in which an intermediate (Intermediate A) is N-deuterated with a suitable acid derivative. Alternatively, the present disclosure The specific compound of the content is obtained by reacting intermediate B with intermediate C or intermediate D to form urea in the final stage. 78 201111360

Intermediate A

Intermediate B

Intermediate C

The compound represented by the intermediate A is produced by reacting the intermediate E with one of the types represented by the intermediate C or the intermediate D. Λ °\^WNH2 , \^·Ν R1

Intermediate C OR Intermediate D

Intermediate E

Intermediate A

The compound represented by the intermediate B is reacted with 2-aminopyridine-4-ol and fluoro-4-nitronaphthalene via SNAr, followed by deuteration of the aminopyridine and reduction of the nitronaphthalene. preparation. F

Intermediate B s 79 201111360 The electrophilic compound represented by intermediate C or intermediate D is obtained from the relevant amine by suitable activation and is usually used without further purification. The 5-aminopyrazole derived from intermediate B and inter-substrate C is derived from a commercial source from which such compounds can be obtained, or prepared using the cited literature methods or by the methods disclosed herein. obtain.

Intermediate A1 : 1-(4-(2-Amino)pyridin-4-yloxy)naphthalene small group Third butyl-1-p-tolyl-1H-pyrazol-5-yl)urea

Add a saturated aqueous solution of NaHC〇3 (14 ml) to a solution containing 3-t-butyl-1-y-p-phenyl-1H-pyrazole-5-amine (WO 2000043384) (206 mg, 0.900 mmol) in DCM (2 〇 ml) of the solution and the mixture was cooled to 0 C and stirred vigorously in a single batch of tri-methylmethyl chloroformate (325 μL, 2.70 mmol). 〇(>c continued to stir vigorously for another 8G minutes. The organic layer was separated and dried and then evaporated in vacuo to give 3·tert-butyl_5-isocyanoindole_p-toluene 201111360-based-1H Pyrazole, intermediate B1 as an orange oil. The material was pumped under high vacuum for 30 min and then extracted into THF (6.0 mL) and stored under nitrogen at EtOAc and used directly in the next step. Containing 4-(4-aminonaphthalen-1-yloxy) 吼_2·amine, intermediate E (116 mg, 0.462 mmol) and DIPEA (240 μL, 139 mmol) in THF (3 ml) of the stirred solution was added to an aliquot of the previously prepared isocyanate solution (2.0 ml, 0.300 mmol) and the resulting mixture was slowly warmed to room temperature. The solution of the ester acid ester in THF was added to the reaction mixture after 1.5 hours (1 mL, 0.150 mmol) and after another 3.5 hours (〇·5 mL, 0.075 mmol). After 20 hours, Water (30 mL) was added and the mixture was evaporated w~~~~~~~~~~~~ After evaporation in vacuo, the crude material thus obtained was purified by flash column chromatography (Si s 2; 12 g, 25-100% [5% MeOH in EtOAc] in iso-heptane. The title compound was obtained as a brown oil. Intermediate A1 (127 mg, 49%): m/z 507 (M+H) + (ES+) Intermediate Β1: Ν-(4-( 4-aminonaphthalen-1-yloxy)acridin-2-yl)-2-decyloxyethylamine

4-(4-nitronaphthalen-1-yloxy)acridin-2-amine

S 201111360 contains 2-amino group.唆 唆 醇 Μ Μ Μ Μ Μ Μ Μ 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 For 3 minutes and then use a solution containing κ fluorocold sylylene (72 gram, milk thistle) in acetonitrile (400 « liters) during 5 〇 | clock. After stirring at room temperature overnight, The reaction was heated for 2 hours. The reaction was sprayed off, but not cooled, and treated with water ΜX 100 mL). The mixture was cooled to 2 hours, warmed and cooled to Gt. The yellow precipitated (iv) was collected by a transfer method and washed with water and a mixture of acetonitrile (1:1, 2×m) and then washed with water (500 ml) to give a compound as a yellow solid (76.0 g, 70%) : m/z 283 (M+H)+ (ES+). Not Imethoxy-Ν-0Κ4-crythylnaphthalenyloxy)Reading _2_yl) acetamide will be cooled in an ice bath Containing 彳4_(4-nitronaphthalenyl)oxy)indole 2_amine (71.8 g, 255 mmol) in anhydrous DCM (swell) and DIPEA (84. ml, 511 mmol) In the search for falling suspension in = minute Room solution of 2-acetyl group Yue gas (35 milliliters, 383 mole pen). The resulting red solution was stirred at room temperature for up to 丨h and then treated with a solution containing NH3 in MeOH (7 Μ, 100 liters); the condensate formed immediately and the reaction mixture was stirred for another 15 minutes and Evaporate in a vacuum. The solid residue was triturated with water (9 mL). EtOAc (EtOAc) /z 354 (M+H)+ (ES+). 82 201111360 N-(4-(4-Aminonaphthalen-1-yloxy)pyridin-2-yl)_2-methoxyacetamide containing 2-methoxy-indole-(4-(4- Nitronaphthalen-1-yloxy)σ 唆_2_yl)acetamide (5 〇·0 g, I42 mmol) in DMF (5 liters) solution, added to the batch under nitrogen Palladium charcoal (10% w/w pd/c, 5 gram ' 14.15 Torr) and the mixture was washed with hydrogen and maintained under micro-positive hydrogen pressure for 48 hours. The catalyst was removed by filtration through a hydrazine salt and the pad was washed with DMF (2 X 100 mL) and then DCM (100 mL). The solvent was removed in vacuo to give a dark brown residue. <EMILY> Toluene (1 mL) was added and evaporated to remove residual water. After drying overnight under vacuum, the title compound was obtained from EtOAc (EtOAc: EtOAc) + (ES+). Intermediate E: 4-(4-Aminonaphthalen-1-yloxy)pyridine-2-amine [Pathway 1]

Pyridine-4-yloxy)naphthalene-1.amine

S 83 201111360 at 20 C containing 2-chloro-4-|^ ratio bite (1.26 g, 9.58 mmol) and 4 amino-1-neine hydrochloride (? 5 〇 mg, 3 gram of millimolar A third butanol clock (1.29 gram, 11.5 〇 ί) was added to the NMP (4 G ML) solution. The reaction mixture was warmed to EtOAc (EtOAc) (EtOAc &lt The combined organic extracts were washed with brine (15 g EtOAc), dried and evaporated. The crude product was subjected to a snap capture and elution eluted with a solution containing 1% Nii3KMe〇H and the solvent was removed in vacuo to give the title compound as a brown solid (1.02 g, 92%): m/z 271 (M +H)+ (ES+). 4-(2-chloropyridin-4-yloxy)naphthalene_1-N,N-di-tert-butylaminoformate containing 4-(2-chloropyridin-4-yloxy)naphthalene _1_Amine (1.02 g, 3 76 mmol) in THF (30 mL) was added DMF (34 mg &lt;RTI ID=0.0&gt;&gt; Ester (0.904 g, 4-14 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and then warmed to room temperature. After 5 hours, the mixture was cooled to 〇 ’ ' and additional bis-tert-butyl hydrocarbonate (0.904 g, 4.14 mmol) was added. The resulting mixture was stirred at 0 ° C and then at room temperature for 15 minutes. After 16 hours, the reaction mixture was diluted with EtOAc EtOAc. The combined organic extracts were washed with brine (75 mL) dried and evaporated in vacuo. The crude material was purified by flash column chromatography (EtOAc: EtOAc (EtOAc:EtOAc) 〇·892 g, 48%): m/z 471 (M+H)+ (ES+). 4-(4-(N,N-di-t-butylaminomethylindenyl)naphthalene·ι·yloxy)pyridin-2-ylaminocarbamic acid tert-butyl ester will contain 4-(2-chloro ° 咬-4-yloxy)naphthoquinone-di-t-butylaminocarbamic acid J (4) (0.892 g ' 1.894 mmol), butyl butyl methacrylate (0.666 g ' 5.68 mil Mohr) 'carbonate planer (〇 926 grams, 2.84 millimolar), Pd2 (dba) 3 (〇.〇43 g, 0.047 mmol) and XantPhos (0.055 g, 0.091 mmol) The mixture was suspended in THF (10 mL). The reaction mixture was thoroughly washed with nitrogen' and then heated under reflux. After 15 hours, the mixture was cooled to EtOAc (EtOAc m. The combined organic extracts were washed with brine (50 mL) dryness The crude material was purified by flash column chromatography (EtOAc EtOAc EtOAc (EtOAc) Mg, 28%): m/z 552 (M+H)+ (ES+). Intermediate E: 4-(4-Alanylnaphthalenyl)pyridin-2-amine containing 4-(4-(N,N-di-t-butylamino)indolyl]第三_基 oxy)pyridin-2-ylamino decanoic acid tert-butyl ester (289 mg, 0.524 mmol) was added to a stirred solution of DCM (8 liters) to TFa. The resulting mixture was stirred for 1 hour after being slowly warmed to room temperature, and the volatiles were removed in vacuo and the residue was extracted in Me〇H (5 mL) for SCX capture and release. It was eluted with a solution containing 1% 85 1 201111360 NH3 in MeOH. The solvent was removed in vacuo to afford compound <RTI ID=0.0>#</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Intermediate E: 4-(4-Aminonaphthalen-1-yloxy)pyridin-2-amine [Pathway 2]

Will contain 4-(4-stone succinyl-1-yloxyl octa-2-amine (2.00 g, 7.11 mmol) in decyl alcohol (70 mL) <DCM (70 mL) The solution in the mixture was hydrogenated by Thales H-cube (1.0 ml min-1, room temperature, 55 mm 10% Pt/C Cat-Cart' all hydrogen mode) and then Evaporation in vacuo. EtOAc (EtOAc)EtOAc.EtOAc. Purification by flash column chromatography (Si 〇 2, EtOAc EtOAc (EtOAc)克, 85%) 'Intermediate E; Rt 1.04 min (method 2); m/z 252 (M+H) + (ES+). Example 1: N-(4-(4-(3-(3-) Tributyl-p-phenylene*_1H_pyrazole-5-yl)-yl)-naphthalen-1-yloxy)-pyridyl)-2-(2-methoxyethoxy)acetamide 86 201111360

To a solution of intermediate A1 (50 mg, 0.099 mmol) and DIPEA (86 μL, 0.493 mmol) in anhydrous THF (3 mL) 2-decyloxyethoxy)acetamidine (6 〇 2 mg, 0.395 mmol) and the reaction mixture was maintained in hydrazine. (: for 3 minutes and then warmed to room temperature. After 3 hours, the reaction was quenched by the addition of 1% NH3 in MeOH (2.0 mL) and the mixture was Evaporation in vacuo. Purification of the residue by flash column chromatography (EtOAc, EtOAc, EtOAc (EtOAc) The title compound was obtained as a white solid (40 mg, 62%), Example 1; Rt 2.56 min (method 2); m/z 623 (M+H)+ (ES+); lH NMR (400 MHz, DMSO-d6) δ ·· 1.28 (9H, s), 2.40 (3H, s) ' 3.27 (3H, s) ' 3.47 (2H ' m), 3.62 (2H ' m), 4.05 (2H, s), 6.41 (1H, s ), 6.71 (1H, dd), 7.35_7·38 (3H, overlap with m), 7.46 (2H, m), 7.57 (1H, m), 7.64-7.66 (2H, overlap with m), 7.84 ( 1H, dd), 7.97 (1H, d), 8.09 (1H, d) ' 8.20 (1H, d), 8.79 (1H, br s), 9.12 (1H, br s), 9·95 (1H, br s s 87 201111360 Example Heart (4·(4·(3-(tetra)tributyl.l-p-tolyl^-)-glycosyl)naphthalene·ι.

In a suspension containing tetrahydro-2H-n-butan-4-o-acid (38·5 mg, 296 296 mmol) in anhydrous DCM (3.0 mL). Oxalic acid gas (29. 2 microliters, 〇·345 millimoles) was added under nitrogen, and the mixture was maintained for 2 g minutes and then warmed to room temperature. After 1 hour, the mixture was cooled to 〇t: and Intermediate A1 (50 mg, 0.099 mmol) and DIPEA (86 μL, 493 493 mmol)

Ear) join. The reaction mixture was kept at 〇 for 3 且 and then warmed to room temperature and after 2.25 hours, it was quenched by the addition of 1% NH3 in Me〇H / gluten (2.0 liters). The resulting mixture was evaporated in vacuo after another minute and the residue was subjected to snap capture and release. The crude product thus obtained was purified by flash column chromatography (Si.sub.2, 12 g, 5% MeOH in EtOAc) The title compound was obtained as a white solid (25 mg, 41%), mp. ield: ield: 2.43 min (method 2); m/z 619 (M+H)+ (ES+); lH NMR (400 MHz, DMSO-d6) δ : 1.29 (9H, s), 1.48-1.64 (4H 'overlaps with m), 2.40 (3H, s), 2.68 (1H ' m), 3.27 (2H, dt), 3·84 (2H, m), 6 ·4ι 88 201111360 (1H ' s) ' 6.71 (1H,dd) ' 7.33 (1H,d),7.38 (2H,d)7.47 7.84 (1H ' dd) ' 7.97 (1H,d),8.09 (1H,d ), 8.18 (1H, d), 8.62 (1H, brs), 9.14 (lH, brs), 10.49 (lH, brs). Example 3 · N-(4-(4_(3-(3-tert-butyl-p-p-tolyl-1H") than naphthyl-1)-yloxy) 比 咬_2_ Base peak (methylthio)

(2H 'd) '7·57 (1H,m),7 65 (1H,m),7 67 (1H, phantom, containing 2·(曱thio)acetic acid (28.4 μl, 〇.326 mmol) In a solution of anhydrous DCM (3.0 mL) under nitrogen and hydrazine. oxalic acid gas (32.2 liters, 0.380 mM) was added and then DMF (1 drop) was added and the mixture was maintained at (TC up to 2G) After a few minutes and then warmed to room temperature. After 1 hour, the mixture was cooled to 〇〇c and intermediate A1 (55 mg, 0.109 mmol) and DIPEA (95 μL, 〇M3 mmol) were added. The reaction mixture was kept at 〇c for 3 且 minutes and then warmed to room temperature and after 3 hours, it was quenched by adding a solution containing 1% NH3 in Me〇H (3.0 liters). After another 16 hours, The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si2, 12 g, containing [5 〇 /0 Me〇H in Et 〇Ac] in isohexane , 0-60%, gradient elution) was purified. The product thus obtained was subjected to SCX capture and release and then repurified by flash column chromatography (Si〇2 '12 g' containing [5% MeOH in EtOAc]

S 89 201111360 hexanes, 0-55%, gradient eluted to give the title compound as a white solid (12 mg, 18%), Example 3; Rt 2.57 min (method 2); m/z 595 (M+ H)+ (ES+) ; lH NMR (400MHz, DMSO-d6) δ: 1.28 (9H, s), 2.09 (3H, s), 2.40 (3H, s), 3.27 (2H, s), 6.41 (1H, s), 6.66 (1H, dd), 7.34 (1H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (1H, m), 7.63-7.67 (2H, overlap with m), 7 · 84 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.18 (1H, d), 8.82 (1H ' br s), 9.15 (1H, br s), 10.62 (1H, br s). Example 4: N-(4_(4-(3-(3-tert-butyl-p-p-phenylene-mn-pyrazolyl)glycosyl)-naphthalen-1-yloxy)° ratio -2- base) -3-methoxypropanamide: RV001148

In a solution containing 3-methoxypropionic acid (30.6 μL, 0.326 mmol) in anhydrous DCM (3.0 mL). Add grasshopper &amp; (32.2 microliters, 0.380 millimoles) under nitrogen and then add DMF (1 drop). The mixture was maintained at 0 C for 20 minutes and then warmed to room temperature. After 丨 hours, the mixture was cooled to o ° c and intermediate A1 (55 mg, 0.109 mmol) and DIPEA (95 μL, 0.543 mmol) was added and the reaction mixture was stored at 0 ° C For 30 minutes and then warmed to room temperature. After 2 hours, the reaction was quenched by the addition of 1% NH3 in Me.H. The residue was purified by flash column chromatography (EtOAc, EtOAc (EtOAc: EtOAc) Solid target compound (35 mg '53%), Example 4, Rt 2.43 min (Method 2); m/z 593 (M+H) + (ES+); lH NMR (400 MHz, DMSO-d6) δ: 1.28 ( 9H, s), 2.40 (3H ' s), 2.55 (2H, t), 3.18 (3H, s), 3.51 (2H, t), 6.41 (1H, s), 6.70 (1H, dd), 7.33 (1H , d), 7.38 (2H, d) ' 7.47 (2H, m), 7·57 (1H, m) ' 7.64-7.66 (2H, overlap with m), 7.84 (1H, dd), 7.97 (1H, d ), 8.09 (1H, d), 8.18 (1H, d), 8.81 (1H, br s), 9.13 (1H, br s), 10.53 (1H, br s). Example 5: N-(4-(4-(3-(3-Tert-butyl-1-p-tolyl-1H-0-biazole-5))ureido)naphthalen-1-yloxy)tonidine-2羟基-)-2-hydroxyacetamide

Add a grasshopper gas (28.6 μl, 0.339 mmol) to a suspension containing acetoxyacetic acid (34.3 mg, 0.290 mmol) in anhydrous DCM (1.5 mL) under nitrogen and then add DMF (1 drop) and the mixture was maintained in hydrazine. Twice for 20 minutes and then warmed to room temperature. After 1 hour, the mixture was cooled to 0 ° C and a solution containing Intermediate A1 (49 mg &lt;RTI ID=00&0&gt;&gt; The reaction mixture was maintained at hydrazine for 3 min and then warmed to room temperature and after 2.75 h, quenched with a mixture of &lt After the other hour, the volatiles were evaporated in vacuo and the residue was purified by flash column chromatography (Si.sub.2, 12 g, containing 5% MeOH in EtOAc). -70%, gradient elution) was purified. The product thus obtained was subjected to SCX capture and release and then re-purified by flash column chromatography (Si 〇 2, 12 g, containing [5% MeOH in EtOAc] in iso-hexane, 0- 70%, gradient elution) gave the title compound as a white solid (11 mg, 20%), Example 5; Rt 2.25 min (method 2); m/z 565 (M+H)+ (ES+); iH NMR (400MHz, DMSO-d6) δ : 1.28 (9H, s), 2.40 (3H, s), 3.96 (2H, d), 5.64 (1H, t), 6.41 (1H, s), 6.72 (1H, dd) , 7.35 (1H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (1H, m), 7.65 (2H, m), 7.83 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.19 (1H, d), 8.81 (1H, br s), 9.14 (1H, br s), 9.75 (1H, br s). 3-isopropyl-1-p-tolyl-1H-pyrazole-5-amine

To a mixture of acetonitrile (0.50 ml '9.57 mmol) in THF (30 mL) was added at room temperature at room temperature with potassium 2-mercaptobutan-2-ol (1.7 M solution in 2-mercapto-butan-2-ol) Medium, 16.9 ml, 28.7 mmol. After the addition of 92 201111360 was completed, ethyl isobutyrate (5·1 2 ml, 38·3 mmol) was added dropwise and the mixture was maintained at room temperature for 16 hours. The reaction mixture, which was concentrated in vacuo to ca. 20 mL, was diluted with ethanol (2 mL) and p-toluene-hydrochloride (1.52 g, 9.57 mmol) was added. The mixture produced by D Hai was acidified to pH 1 by adding concentrated hydrochloric acid and then the mixture was heated to 70 Torr for 2 hours. The mixture was cooled to room temperature and concentrated to about 20 mL in vacuo and then diluted with water (3 liters). The aqueous mixture was adjusted to pH 12 by aqueous Na.sub.2H (6M) and then extracted with EtOAc (2.times.20 liters). The combined organic extracts were washed with EtOAc EtOAc (EtOAc m. 32 minutes (method 2); m/z 216 (M+H)+ (ES+). This material was used directly in the next step without further purification. Example 6: Ν-(4-(4-(3·(3-isopropyl-1-p-tolyl·ιη_τι _5_ yl)))))) 2-methoxyacetamide

To a stirred solution containing CDI (113 mg, 0.696 mmol) in DCM (2 mL) was added 3-isopropylpyridinium phenyl-ih_u to a 5-amine (176 mg, 90% purity) , 0.737 millimoles) and the mixture was maintained at room temperature for 3 hours. Will contain intermediate B1 (9〇 mg, 0.278

S 93 201111360 millimolar) was added to a solution of DCM (1. 2 liter) and the reaction mixture was maintained at room temperature for a further 16 h and then distributed between DCM (15 mL) and water (15 mL). The organic layer was separated and washed with brine (15 mL) then dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si.sub.2, EtOAc (EtOAc) EtOAc (EtOAc) The title compound (32 mg '20%) was obtained as a pale pink solid, Example 6; Rt 4.80 min (Basic Method ι); ιη/ζ565 (M+H)+ (ES+); lH NMR (400 MHz, DMSO -d6) δ : 1.24 (6H,d), 2.40 (3H,s), 2.89 (1H,m), 3.30 (3H,s), 3.99 (2H,s) ' 6.37 (1H,s) ' 6.70 (1H , dd), 7.34 (1H, d) ' 7.38 (2H,d) ' 7.46 (2H,d), 7.57 (1H,m), 7.63-7.674 (2H, overlapping with m), 7.84 (1H,d), 7.97 (1H,d), 8.09 (1H, d)' 8.19 (lH'd)' 8.81 (1H, s) '9.13 (1H, s), 10.04 (1H, s). 3-ethyl-1-p-tolyl-1H-pyrazole-5-amine

To a solution of acetonitrile (0.50 liters, 9.57 mmol) in THF (30 mL), EtOAc (EtOAc) · Alcohol in '16 9 ml' 28 7 mmoles). After the addition was completed, propionic acid (4.40 liters, 38.3 millimoles) was added dropwise and the mixture was maintained at room temperature for 16 hours. Mix the reaction mixture on the true 94 201111360

The mixture was adjusted to pH 12 by adding aqueous NaOH (6M) and then extracted with diethylamine (2.times.20 mL). The organic extracts were combined, concentrated in a pad of EtOAc (EtOAc) (EtOAc) (EtOAc) (EtOAc) The residue separation method (Si〇2' containing EtOAc in isohexane water (30 ml) was washed, dried (MgS〇4)_gj by flash column chromatography (Si〇2, medium, 0-50 %, gradient elution) was purified to give the title compound (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; Ν-(4-(4-(3-(3-ethyl-1-p-tolylpyrazole-5(yl))))-yl-1-yloxy)° 咬-2-yl)-2 -methoxyethylamine

Add 3-ethyl-1-p-tolyl_ΐΗ_σ-biazole-5-amine (140 mg, 0.696) at room temperature in a suspension containing CDI (113 mg '0.696 house moles) in dcm (2.0 liter) A solution of the intermediate Β1 (120 mg, 0.371 mmol) in DCM (1.6 mL). The reaction mixture was maintained at room temperature for an additional 16 hours and then distributed between DCM (15 mL) and water (15 mL). will have

S 95 201111360 The layers were separated and washed with brine (15 mL), dried (MgS 〇 4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si2, EtOAc (EtOAc) elute The title compound (90 mg, 35%), mp. 1.21 (3H, t), 2.40 (3H, s), 2.57 (2H, q), 3.30 (3H, s) ' 3.99 (2H, s), 6.36 (1H, s), 6.70 (1H, d), 7.33 -7.39 (3H, overlap with m), 7.46 (2H, d), 7.57 (1H, t), 7.63-7.67 (2H, overlap with m), 7.84 (1H, d), 7.97 (1H, d), 8.09 (1H, d), 8.18 (1H, d), 8.82 (1H, s), 9.13 (1H, s), 10.05 (1H, s) o Example 8: N-(4-(4_(3-(3-) Tert-Butyl-1-p-tolyl-1H-indazol-5-yl)ureido)naphthalen-1-yloxybenzil-2-yl)-2-decyloxyacetamide

3-Tributyl-1-p-tolyl-1H-pyrazole-5-amine was added portionwise over 1 hour in a suspension containing CDI (32.5 g '200 mmol) in dry DCM (300 mL) (WO 2000/043384) (46.0 g, 200 mmol) and the mixture was stirred at room temperature for 2 hours and a yellow solution was formed over the time of the 2011 201111360. The whole intermediate containing intermediate w (220 mL) was added dropwise over a period of 2 min to a solution containing &lt;RTI ID=0.0&gt; The mixture was stirred at room temperature for 18 hours and ethanol (5 〇.^ = liter) was added. After an additional 1-5 hours, the solvent was removed in vacuo to give a purple oil, which was dissolved in Et0Ac (1. liter) and sequentially with saturated solution (2 X 250 mL), water (2 x 250 mL) Wash with saline (2 毫升 ml) and then dry (MgS〇4). The solvent was transferred under vacuum to give a dark red viscous oil (75 g). It was purified by EtOAc EtOAc (EtOAc:EtOAc) This material was combined with a second batch (129 g total) which was recrystallized from a mixture of iso-hexane/EtOAc (2: 5 &lt;Recycled); m/z 579 (M+H)+ (ES+): Old NMR (400 MHz, DMSO-d6) δ: 1.29 (9 Η 's), 2.40 (3 Η, s), 3.31 (3 Η, s), 3.99 (2 Η, s), 6.41 (1 Η, s), 6.70 (1 Η, dd), 7.33-7.39 (3 Η, m), 7.46-7.48 (2 Η, m), 7.58 (1 Η,ddd), 7.63-7.67 (2 Η,m), 7.84 (1 Η,dd),7.97 (1 Η,d),8.10 (1 Η,d),8.19 (1 Η,d),8.79 (1) Η, s), 9.13 (1 Η, s), 10.03 (1 Η, s). 3-(1-(Benzyloxy)-2-methylpropan-2-yl)-1-p-tolyl-1H-pyrazole-5-amine 97 £ 201111360

OBn

芑 芑 虱 1.6 (1.62 g, 60% w/w suspension in mineral oil, 40.5 mmol) in a suspension of toluene (2 〇 ml) was added dropwise during 1 hour at reflux for 1 hour. Methyl 3-(benzyloxy)_2,2-dimercaptopropanoate [European Journal of Organic Chemistry, 2〇〇7 (6) 934-942] (6.00 g, 27.0 mmol) and acetonitrile (2 12 ml) , 4 〇 5 millimoles) in the stupid; valley liquid. The reaction mixture was heated at reflux for an additional 5 hours and then cooled to room temperature. The mixture was acidified to pH 4 with aqueous EtOAc (EtOAc)EtOAc. The organic extracts were washed with water and brine and dried (MgSO4) and evaporated in vacuo to give 5-(octyloxy)-4,4-dimercapto-3-one pentyl Nitrile (7.50 g, 96%): m/z 232 (M+H) + (ES+), which was used in the next step without purification. Will contain p-phenylene hydrazine (1.99 g, 12.6 mmol) and 5-(nutriyloxy)-4,4-didecyl-3-ketovaleronitrile (4.00 g, 13.8 mmol) , 80% purity) in EtOH, heated at reflux for 16 hours and then cooled to room temperature. The mixture was neutralized with aq. aq. The organic extract was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) eluting 60%); Rt 3.05 minutes (basic method 1); m/z 336 (M+H) + (ES+). Other batches of Compound 8 were prepared by the following methods B and C. B. Experimental procedure for Scheme 11 4-(2-chloroacridin-4-yloxy)naphthalen-1-amine (c)

F

Containing 2-chloro-4-fluoroacridine (1.261 g, 9.58 mmol) and 4-amino-1-naphthol hydrochloride (b) (750 mg, 3.83 mmol) in NMP (40 ml) ) in a stirred solution at _2 Torr. (: Potassium tert-butoxide (1.290 g, 11.50 mmol) was added. The reaction mixture was warmed to room temperature. After 2.5 h, the reaction mixture was diluted with water (1 EtOAc) The combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and elution with 1% NH3 in MeOH. The solution was eluted and the solvent was removed in vacuo to give 4-(2-chloropyridin-4-yloxy)naphthalen-1-amine (c) (1.019 g &lt; 92%) as a brown solid: m/z 271 (M+H)+ (ES+) 4-(2-Chloro-pyridin-4-yloxy)naphthalene_1_fan&gt;1-di-t-butylaminocarbamic acid vinegar (4)

201111360 in a stirred solution containing 4·(2-chloropyridin-4-yloxy)naphthalene_ι-amine (c) (i 〇 19 g, 3.76 mmol) in THF (30 mL) c DMAP (0.034 g '0.282 mmol) and then bis-tert-butyl hydrogencarbonate (0.904 g, 4.14 mmol) was added. The reaction mixture was scrambled at 0 °C for 30 minutes and then warmed to room temperature. After 5 hours, the reaction mixture was cooled to hydrazine. 〇, and the other two _ third butyl hydrogencarbonate (0.904 g, 4.14 亳 Mo) was added. The resulting mixture was stirred at 〇 ° C for 15 minutes and then stirred at room temperature. After 16 hours the reaction mixture was diluted with EtOAc EtOAc EtOAc. The combined organic extracts were washed with brine (75 mL), dried and evaporated. The crude material was purified by flash column chromatography (EtOAc EtOAc) eluting eluting eluting啦 -4- -4-yloxy)naphthalene-1_N,N-di-tert-butylcarbamate (4) (0.892 g '48%): m/z 471 (M+H)+ (ES+). 4-(4-(N,N-di-t-butylaminoindolyl)naphthyloxy)pyridin-2-ylaminocarboxylic acid terpene vinegar (e)

Will contain 4-(2-chloropyridin-4-yloxy)naphthalene-1-N,N-di-t-butylamino decanoate (d) (0.892 g, 1.894 mmol), Tert-butyl carbazate (0.666 g, 5.68 mmol), cesium carbonate (0.926 g, 2.84 mmol) 'Pd2(dba)3 (0.043 g '0.047 mmol) and Hillsfoss 100 A mixture of 201111360 (XantPhos) (0.055 g, 0.095 mmol) was suspended in THF (10 mL). The reaction mixture was thoroughly washed with nitrogen and then heated at reflux. After 15 hours, the mixture was cooled with EtOAc EtOAc m. The combined organic extracts were washed with brine (50 mL) dry The crude material was purified by flash column chromatography (EtOAc EtOAc) eluting eluting elut , N-di-t-butylaminomethylmercapto)naphthalen-1-yloxy) ° butyl-2-ylaminocarbamic acid tert-butyl ester (e) (289 mg, 28%): m/ z 552 (M+H)+ (ES+). 4-(4-Aminonaphthalen-1-yloxy)π ratio bite_2_amine (f)

Containing 4-(4-(N, quinone dibutylaminomethylmercapto)naphthalen-1-yloxy)acridin-2-ylamino decanoic acid tert-butyl ester (e) (289 mg , 0.524 mmol) in a stirred solution of DCM (8 mL). 〇 Add TFA (4 ml). The resulting mixture was stirred while slowly warming to room temperature. After 5 hours, the volatiles were removed in vacuo and residue was taken in MeOH (5 mL). The solvent was removed in vacuo to give 4-(4-aminonaphthalenyl)-yloxy)pyridine-2.amine (f) as a brown-orange oil (U6 mg &lt; (M+H)+ (ES+).

S 101 201111360 1-(4-(2-Aminopyridin-4-yloxy)naphthalene small group)_3_(3_Terbutyl-p-p-phenylene-lH-α-biazole-5-yl Urea (h)

A saturated solution of NaHC(R) (14 mL) was added to a solution containing 5-aminopyrazole (g) (0.206 g, 0.900 mmol) in DCM (2 mL). The mixture was vigorously stirred, cooled to 〇〇C and a portion of trichloromethyl carbite (0.326 mL, 2.70 mmol) was added. The reaction mixture was stirred vigorously at 0 °C for an additional 8 min. The layers were separated and the organic layer was dried&apos; evaporated in vacuo and the resulting orange oil was dried in high vacuum for an additional 30 minutes. The isolated isocyanate was then extracted into THF (6 mL) and stored under hydrazine &lt;JC nitrogen. Containing 4-(4-Amino-hydrogenated)-yloxy) bite 2_amine (7) (116 mg, 0.462 mmol) and mpEA (241 μL, 1 385 mmol in THF (3 liter) In the fresh solution, add the whole portion of the pre-formed isocyanide solution (2 ml, σ milligrams), and the resulting mixture is slowly warmed to room temperature and mixed. Cyanate solution (1 ml, Q 15 () millimolar μ hour 102 201111360 was added and added to the reaction mixture after another 3.5 hours (0.5 ml, 0.075 mmol). After 20 hours, water ( The mixture was extracted with EtOAc (2×30 mL).EtOAc. Chromatography (Si 〇 2; 12 g) was purified by eluting with 25 to 100% [5% MeOH in EtOAc] Aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-phenyl-indole-π-quatern-5-yl)urea (h) (127) Mg, 49%): m/z 507 (M+H)+ (ES+). N-(4-(4-(3-(3-Ter-butyl-1-p-tolylyl)- oxazole- 5-base脉))naphthalen-1-yloxy)°pyridin-2-yl)_2_decyloxyacetamide (Compound 8)

Slowly add 曱 基 乙 ( (64·2 μL, 0.703 mmol) to 1-(4-(2-amino-2-indolyl-4-yloxy)naphthyl)_3_(3_ Tert-butyl-1-p-phenylphenyl-1Η-carbazole-1_yl)urea (8) (10 mg mg, 〇m mmol) and DIPEA (153 μl '0.878 mmol) in thF (5 mL) In the mixture. The reaction mixture was stirred at 〇〇C for an additional 2 minutes 103 1 201111360. After 2.5 hours, the reaction was quenched with EtOAc (3 mL) EtOAc. The volatiles were removed in vacuo and the residue was dissolved in MeOH (5 mL) and AcOH (2 mL) and taken for SCX capture and eluted with a solution containing &lt;RTIgt; Purification of the crude material by flash column chromatography (Si 〇 2; 12 g) eluting with EtOAc EtOAc EtOAc EtOAc The N-(4-(4-(3-(3-t-butyl-p-p-tolyl-biazole-5-yl)))-naphthalen-1-yloxy group) was obtained as a white solid. -Methoxy-2-acetamide (Compound 8) (62 mg, 61%): m/z 579 (M+H) + (ES+). lH NMR (400MHz, DMSO-d6) δ : 1.29 (9 Η, s), 2.40 (3 Η, s), 3.31 (3 Η, s), 3.99 (2 Η, s), 6.41 (1 Η, s),6·70 (1 Η, dd), 7.32-7.40 (3 Η,m), 7.44-7.48 (2 Η,m), 7.55-7.61 (1 Η,m) ' 7.63-7.67 (2 Η, m) ' 7.84 (1 Η, dd), 7.97 (1 Η, d), 8.09 (1 Η, d), 8.19 (1 Η, d), 8.79 (1 Η, s), 9.13 (1 Η, s) , 10.02 (1 Η, s). C. Experimental Procedure for Scheme 12 4-(4-Nitronaphthalen-1-yloxy)acridin-2-amine (1)

104 201111360 NaH (60) was added portionwise over a period of 3 minutes in a stirred solution of 2-aminopyridine-4-ol (23.0 g, 209 mmol) in DMF (200 mL). % dispersed in mineral oil, 9.21 g, 23 〇 millimolar). The mixture was warmed to room temperature and cooled to 〇 ° C after 丨 且 and added with 1-fluoro-4-nitronaphthalene (9) (4 g, 2 〇 9 mmol) in DMF (100 ml) ) a solution. The reaction mixture was warmed to room temperature and was diluted with water (1 liter) and extracted with Et EtOAc (3 χ 500 mL). The organic extracts were combined and washed with water (3 χ 700 mL) and brine (500 mL). The yellow precipitate collected by filtration was separated and washed with water (500 mL) and dried in vacuo overnight. The organic layer was dried (MgSO.sub.4), filtered and evaporated in vacuo. The residue was triturated with a mixture of EtOAc (EtOAc) (EtOAc). The supernatant from the upper layer of the method was evaporated in vacuo and the residue was subjected to flash column chromatography (Si 2 , 120 g, containing 30-100% EtOAc in iso-hexane, gradient elution) purification. This product was combined with two solids that were previously isolated, extracted to EtOAc (500 mL) and evaporated in vacuo to afford 4-(4-nitronaphthalen-1-yloxy) Pyridin-2-amine (j) (40.1 g, 65%): m/z 282 (M+H) + (ES+). 2-decyloxy-N-(4-(4-nitronaphthalen-1-yloxy) °pyridin-2-yl)acetamide 00

S 105 201111360 contains 4-(4-decylnaphthalenyloxy). Bisidine-2-amine (1) (4 g, 135 mmol) and DIPEA (48.1 ml, 27 mmol) in DCM (600 mL) in a stirred solution of &lt;&gt;&gt; Ethoxy oxime (18.53 ml, 203 mmol) was added dropwise. The mixture was warmed to warmness and after 1 hour, ammonia solution (1 mL, 7 EtOAc in MeOH) was added and stirring was continued for 30 minutes, during which time a precipitate formed. The mixture was evaporated in vacuo and water (1 L) was taken to residue to afford a red suspension. The glacial acetic acid was added dropwise until the yellow color continued (~5 ml). The solid was collected by filtration and washed with water (300 ml) to give methoxy-N-(4-(4-nitronaphthalen-1-yloxy)n pyridine. Ethylamine (8) (44.1 g, 90%): m/z 354 (M+H)+ (ES+). N-(4-(4-Aminonaphthalen-1-yloxy)π ratio bite-2 base)_2_methoxy ethoxylated amine (1)

Will contain 2-decyloxy-indole-(4_(4_shisocylnaphthalen-1-yloxy)t7-pyridin-2-yl)acetamide (k) (44.0 g, 125 mmol) and iron powder (41.7 g, 747 mmol) heated in a stirred suspension of acetic acid (300 mL) at 45 °C. After 3 hours, the mixture was cooled to room temperature and slowly and carefully poured onto solid Na.sub.2 C.sub.3 (200 g). The mixture violently foamed. The mixture was partitioned between water (500 mL) and EtOAc (500 mL). The aqueous layer was basified to pH 11 with solid Na.sub.2 C.sub.3 and filtered through a pad. The aqueous layer and the celite pad were extracted with EtOAc (3×500 liters) and the combined extracts were washed with EtOAc EtOAc N-(4-(4-Aminonaphthalen-1-yloxy)pyridine-2-yl)-2-methoxyacetamide (1) (35.0 g, 78%): m/z 324 (M+H)+ (ES+). N-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)-n-yloxy)-2- Methoxyethylamine (Compound 8)

In a stirred suspension containing CDI (28.8 g, 178 Torr) in DCM (250 mL), 3 portions of succinimide and p-phenylphenylamine (g) were added portionwise during the hour at room temperature under nitrogen. ) (40.7 grams, 178 moles). After 1 hour, the resulting dark red solution was added dropwise to the N-(4-(4-aminonaphthalenyl-l-yloxy)pyridin-2-yl)_2-methoxyacetamide during the hour. (1) (35.5 g, 99 mmol) in DCM (1 liter), stirred in a solution. After 1 hour, Me〇H (1 mL) was added and the mixture was maintained at room temperature for 16 hours. The reaction mixture was evaporated in vacuo and EtOAc (EtOAc) elute Dry the organic layer

S 107 201111360 (MgS04), which was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc, EtOAc (EtOAc) The product was recrystallized from ethyl acetate / heptane (5:3 v/v mixture, 800 ml) to give a white powder of Ν-(4·(4-(3-(3-tert-butyl-)- 1-p-tolyl·1H_praqin·5-yl) tetyl)naphthalen-1-yloxy)indole-2-yl)-2-methoxyacetamide (compound 8) (25.5 g, 45 %). Found: C, 68.41; Η, 5.93; Ν, 14.36' C33H34N6O4 Requires · C' 68.49, Η' 5.92; Ν, 14 52%. Example 9: N-(4-(4-(3-(3-(l-)-yl-2-mercaptopropen-2-yl)p-p-tolyl-IHH5-yl)-yl)naphthalen-1-yl Oxy) π than bit I)) 2 methoxyacetamide

Addition of 3-(1-(+-yloxy)_2-methylpropan-2-yl)-1-p-tolyl group in a suspension containing CDI (94 mg, 0.580 mmol/DCM (1 mL)) -1H-pyrazole-5-amine (195 mg, 〇58 〇 mmol) in DCM (1. 〇 升) 谷谷液 and the mixture is maintained at room temperature for $ hours. Contains intermediate B1 (100 mg '0.309 mmol) was added to a solution of (1.6 mL) and the 5 hr reaction mixture was maintained at room temperature for an additional 16 hours. Another portion of the pyrazole CDI adduct was added, intermediate D3 ' CDI (30 mg, 0.18 mmol) and pyridinium (6 mg, 108 201111360 0·18 mol) were prepared and the mixture was maintained at room temperature for 24 hours and then distributed in DCM (15 mL) and Between water (15 ml), the organic layer was washed with brine (15 ml) and dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si. It is purified by Et~Ac in isohexane, 30-1% by weight, gradient elution and then milled from methanol to give N-(4_(3_(3_(3_(3_(3)氧基oxy)-2-methylpropan-2-yl;)-p-toluene - 丨沁pyrazine, ureido)naphthalen-1-yloxy)pyridine_2•yl)_2-methoxyacetamide (ιι〇 mg, 40%); Rt 2.86 min (Method 2); m/z 685 (M+H)+ (ES+). This material was used directly in the next step (as follows) containing HBr in acetic acid (45% w/v) in a solution containing the previously obtained benzyl test (98 mg, 0.143 mmol) in acetic acid (3.0 ml). , 181 μl, 1.431 mmol, and the reaction mixture was maintained at room temperature for 16 h. The mixture was diluted with water (15 mL) and basified to pH 9 (2M NaOH) and ethyl acetate (2×l 5 mL) Extraction. The organic extracts were combined, washed with brine (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc In the alkane, 30-100%, purified by gradient elution to give 2-(5-(3-(4-(2-(2-methoxyethyl)amino)) as a pale pink solid. Naphthyl)-naphthyl)-ureido)-indole-p-phenyl-pyridyl-1-pyrazol-3-yl)-2-mercaptopropyl acetate (65 mg, ; Rt (Μ min (basic method) ;m/z 637 (Inspection + (ES+). This material is used directly in the next step (see below). 109 201111360 有 有 到 之 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ .085 莫耳) 〇170真苴 and 彳 u u Add potassium carbonate (23.4 mg, 4 ears) in green 5 ml) to maintain at room temperature for 3 hours m / side should commit the mouth 0 085 ancient The seedlings were added with additional potassium acid citrate (11.7 mg, Θ )) and the sterol was added to the vacuum in the next hour, and hJC (10 mL) was added. The mixture was used for (10) &amp; 1 〇 liter) extraction and the combined organic extracts were washed with brine (1 mL) and then dried (MgS 〇 4) and evaporated in vacuo. The residue was purified by flash column chromatography ( Si〇2, EtOAc in isohexane, eg -10%, gradient elution) was purified to give a pale pink solid (4-(4-(3-(3-(1-hydroxy-2-) _Methylpropane-2_yl)-1-p-tolyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)-2-methoxy B Indoleamine (33 mg, 65%) 'Example 9; Rt 4.50 min (Basic Method 1); m/z 595 (M+H)+ (ES+); lH NMR (400 MHz, 〇MSO-d6) δ: 1.21 ( 6H, s), 2.39 (3H, s), 3.29 (3H, s), 3.44 (2H, d), 3.98 (2H, s), 4.61 (1H, t), 6.41 (1H, s), 6.70 (1H ,d),7 .33-7.39 (3H, overlap with m), 7.46 (2H, d), 7.57 (1H, t), 7.63-7.66 (2H, overlap with m), 7.83 (1H, d), 7.96 (1H, d) , 8.08 (1H, d) ' 8.18 (1H, d), 8.81 (1H, s), 9.12 (1H, s), 10-06 (1H, s). 3-tert-butyl-i_(2,3,5,6-tetramethyl-4-(trimethyl)phenyl)_ih-pyrazole-5-amine 110 201111360

Nd2 1.NaN02/HC|

2. Na2S03 D 3 I

Add sodium nitrite dropwise at a concentration of 壬氖4_toluidine (3 69 g, 31 in AcOH (25 ml) and hydrochloric acid (1 M, 12 ml). 2 52 g, 36 5 mmoles in water (12 liters). The reaction mixture was stirred for 3 〇 8 and then at G. (: slowly added to sodium sulfite (9 21 g) , in the solution of water (2 ml). The mixture was heated to room temperature after 〇 = 3 〇 and then added with hydrogen acid (1 Μ 2 〇 ml small days after the reaction mixture in the room) Concentrate in a vacuum, and then, after scooping 20 ml of water, the sedimentation of the temple is formed. Add the mixture.

Et2 〇 _ ml) and the target was collected by filtration and washed with Et2 〇 (2 GG ml) and then dried to give a blush 2 . 3,5,6· slightly 4·(trimethylene)phenyl 0 well hydrogenated (.g, 7〇%); Rt 2.49 minutes (basic method 1); m/z was not observed. Will contain 4, cardinyl-3-ketovaleronitrile (3.64 g, 29.1 mmol) and 2,3"5:6-tetra-air ice (trimethylmethyl) phenylmorphine hydrogen Ο.8克, 26.5 mmol) was heated to reflux for 16 hours in a solution containing a mixture of hydrochloric acid (2.91 mL, 10M, 29.1 mmol) and EtOH (15 liters). After cooling the reaction mixture to a room temperature, it was purified to a pH of 12 with a 2M NaHH solution (about 100 mL) under cooling (ice-water bath) to maintain the internal temperature and temperature at 2 〇 25 〇c. Use this mixture for the continent

S 111 201111360 ml) extraction and washing of the ether extract with water (2 x 200 ml). The water was combined and extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was recrystallized from isohexane (50 ml) to give a crude compound (1.5 g). The whole part (8 mg) was purified by flash column chromatography (Si EtOAc, 40 g, EtOAc in hexanes, 0-30% gradient elution) The title compound was obtained as a yellow solid (400 mg, 6%); Rt 4.16 min (bass method 1); m/z 237 (M+H) + (ES+). Example 10: N-(4-(4-(3-(3-tert-butyl-i-(2,3,5,6-tetradecyl-4-(trimethyl)phenyl)HH-« ratio Zin-5-yl)ureido)naphthalene·ΐ-yloxy)π-pyridyl-2-yl)-2-methoxyacetamide

In a stirred suspension containing CDI (144 mg, 0.888 mmol) in DCM (1. mM), was added with 3 -3 - butyl - 1 - (2, 3, 5, 6 - 4 A solution of 氘-4-(trimethyl)phenyl-pyrazole-5-amine (210 mg, 0.888 mmol) in DCM (2 mL) and the mixture was maintained at room temperature for one hour. A solution containing the intermediate β1 (180 mg '0.557 mmol) in DCM (1 - 0 mL) was added to the mixture in a single batch and after another one hour, Me 〇H (0.5 mL) was added and the reaction mixture was Concentrate in vacuo (to ~1 s 112 2 〇 1 Hl 36 liters) ^ Residue by flash column chromatography (si 〇 2, 4 g, EtOAc in isohexane, o-ioo. Purified by gradient elution and then recrystallized from heptane / EtOAc to give the title compound (125 mg, 45%) as an off-white solid, Example 1 〇; Rt 5 18 (Basic Method 1) ' m/z 587 (M+H)+ (ES+) ; 1h NMR (400MHz, DMSO-d6) δ : 1·29 (9H ' s) ' 3.31 (3H,s) ' 3.99 (2H, d) ' 6.42 (1H ' s ) ' 6.69 (1H ' dd), 7·34 (1H, d), 7·59 (1H, m) ' 7.65 (2H ' m) ' 7.84 (1H ' d) ' 7.97 (1H,d),8.09 (1H, d)' 8.18 (1H,d)' 8.79 (1H,s),9,13 (ih,s), 10.02 (1H, s). Other examples of the present disclosure are prepared by a process in which intermediate A is converted to intermediate F followed by intermediate F with an amine.

R2 intermediate FI: Ν-(4-(4_(3-(3·t-butyl-1-p-tolyl-sulphonium-5-yl)indolyl)naphthalenyloxy)pyridinyl) _2_ chloroacetamide 113 201111360

To a solution of intermediate A1 (488 mg, 0.963 mmol) and DIPEA (755 μL, 4.33 mmol) in dry THF (25 mL) Microliter, 3.37 millimoles). The reaction mixture was maintained at 0 °C for an additional 30 minutes and then warmed to room temperature. After 1.5 hours, the reaction was quenched with EtOAc (EtOAc)EtOAc The residue was purified by flash column chromatography (40 g, EtOAc (EtOAc EtOAc) The title compound (527 mg, 69%, 73% purity), mp. Example 11: N-(4-(4-(3-(3-tert-butyl-1-p-tolyl_lH-°bazol-5-yl)ureido)naphthalenyloxy)acridine_ 2_base)_2_hoofolinolamine

Adding morphine to a solution containing intermediate F1 (5 mg, 0.086 mmol) and DIPEA (26.1 μL, 150. 150 mmol) in anhydrous THF (3 mL) 131 μl, 015 〇 millimoles 114 201111360 and the mixture was maintained at 〇 for 30 minutes and then at room temperature for 22 hours. The resulting mixture was cooled to 0.degree. C. and an additional portion of &lt;RTI ID=0.0&gt;&gt;&gt; The residue was subjected to scx capture and release and the crude product thus obtained was subjected to flash column chromatography (Si 〇 2 ' 12 g' containing [5% MeOH in EtOAc] in iso-hexane, 0-85 %, gradient elution) was purified to give the title compound as a white solid (16 mg, 29%), </ RTI> </ RTI> </ RTI> Rt 2.22 min (method 2); m/z 634 (M+H)+ (ES+); NMR (400MHz, DMSO-d6) δ : 1·28 (9H, s), 2.40 (3H, s), 2.48 (4H, m), 3.11 (2H, s), 3.59 (4H, t), 6.41 (1H ,s),6.71 (1H,dd),7.33 (1H,d) ' 7.37 (2H ' m),7·47 (2H,m),7.57 (1H,m),7.64-7.66 (2H, overlapping with m ), 7.83 (1H, dd), 7.97 (1H, d), 8.10 (1H, d), 8·19 (1H, d), 8.82 (1H, br s), 9.15 (1H, br s), 9.98 ( 1H, br s). Example 12: N-(4-(4-(3-(3-t-butyl-p-p-tolyl)-pyridin-5-yl)ureido)naphthalen-1-yloxy)pyridine_2_ Base) _(dimethylamino)acetamide

To a solution of intermediate F1 (50 mg, 0.086 mmol) and DIPEA (44.8 μL, 0.257 mmol) in dry THF (3 mL) In THF, 643 μl, 115 £ 201111360 1.29 mmoles and the mixture was maintained for 20 minutes and then warmed to room temperature. After 19 hours, the mixture was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc, EtOAc (EtOAc) %, gradient elution) was purified to give the title compound (13 mg, 26%) as </ RTI> as </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; NMR (400MHz, DMSO-d6) δ: 1.28 (9H, s), 2.25 (6H, s), 2.40 (3H, s), 3.04 (2H, s), 6.41 (1H, s), 6.70 (1H, dd ), 7.34 (1H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (1H 'm) ' 7.64-7.67 (2H 'overlap with m), 7.84 (ih, dd) ' 7· 97 (1H,d), 8.09 (1H,d), 8.18 (1H,d),8.82 (1H, br s) ' 9.15 (1Ή, br s), 9.90 (1H, br s). Example 13: N-(4-(4-(3-(3-tert-butyl-l-p-tolyl_111-pyrazol-5-yl)))-naphthalenyloxy)) 2_yl)_2_(2-methoxyethylamino)acetamide

MeO,

Intermediate F1

DIPEA NH2

Example 13 A solution containing intermediate F1 (50 mg, 0.086 mmol) and 〇ΙρΕΑ (59.7 μl, 0.343 mmol) in anhydrous THF (3 liters). Ethylamine (89 μL, 耄mol). The reaction mixture was maintained in hydrazine. (: up to 3 minutes and then warmed to room temperature and after 19 hours an additional portion of methoxymethoxyethylamine (45 microliters, 0.520 millimoles) was added. The mixture was maintained at a temperature of 116 201111360. Evaporation in vacuo. The residue was purified by flash column chromatography (Si2, 12 g, 5% MeOH in EtOAc) Purification afforded the title compound (14 mg, 25%), mp., mp. DMSO-d6) δ : 1.28 (9H, s), 2.40 (3H, s), 2.64 (2H, t), 3.21 (3H, s), 3.24 (2H, br s), 3.35 (2H, t) ' 6.41 (1H, s) ' 6.71 (1H, dd), 7.34 (1H, d), 7.38 (2H 'd) ' 7.47 (2H ' m), 7.57 (1H, m), 7.64 - 7.66 (2H, with m weight $), 7.83 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.18 (1H 'd) ' 8.81 (1H ' br s) ' 9.14 (1H, br s), 10.21 (1 H, br s). Other examples of this disclosure are by converting the intermediate A to the intermediate G' and then by N. Method preparation.

Intermediate G1. 2-Amino-indole-(4-(4_(3_(3_t-butyl)-p-tolyl-1Η-η-saltyl)ureido)) Ethylamine

117 S 201111360

Contains 2-(t-butoxycarbonylamino)acetic acid [Boc-Gly-〇H] (415 克克' 2.37 mmol), pyB〇p (i.23 g, 2.37 mmol) and DIPEA (413 μL, 2.37 mmol) in a mixture of anhydrous DMF (12 mL), Intermediate A1 (300 mg, 0.592 mmol), and the mixture was warmed to 5 〇 °c Up to 16 hours. The resulting mixture was cooled to rt EtOAc (EtOAc)EtOAc. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by flash column chromatography (40 g, EtOAc (EtOAc:EtOAc) (4-(3-(3-Tert-butyl-1-p-phenylene-1H-indazol-5-yl)ureido)naphthalen-1-yloxy)&gt;bipyridyl-2-yl Amino) 2,2-ketoethylaminocarbamic acid tert-butyl ester (197 mg, 92% purity, 46%); Rt 2.65 min (Method 2); m/z 664 (M+H)+ (ES+). Containing 2-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1Η-η-biazole-5-yl)ureido)-naphthalenyloxy)n-pyridinium_ 2_Amino)-2-ketoethylamine decanoic acid tert-butyl ester (187 mg, 92% purity, 0.259 mmol) in anhydrous DCM (6 mL) in EtOAc c. TFA (2.0 mL) was added under nitrogen and the mixture was maintained at <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The resulting mixture was evaporated in vacuo and purified title title m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m /z 564 (M+H)+ (ES+). Example 14: N-(4-(4-(3-(3-Tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)))-i-yloxy)pyridine 2_base)_2_yl acetamide

To a solution of the intermediate G1 (35 mg, 62 mmol) in anhydrous DCM (2.5 mL), EtOAc (EtOAc, EtOAc) The reaction mixture was maintained at 〇 for 15 minutes and then warmed to room temperature. After 2.25 hours, the mixture was cooled to 〇 ° C and an additional portion of tri-ethylene acetyl isocyanate (4 〇 microliters, 31 mmol) was added. After an additional hour, the reaction was quenched with a solution (1 mL) EtOAc (EtOAc) The residue was subjected to SCX capture and release and the crude product thus obtained was purified by flash column chromatography (Si 2 , 12 g, containing [5% MeOH in EtOAc] in isohexane, 5 〇 1 〇〇 0 / 〇, gradient elution) was purified to give the title compound as a beige solid (16 mg, 4 〇%) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Rt 2. 〇 6 min (method 2); m/z 6〇7 (m+H)+ (ES+); old NMR (400MHz 'DMSO-d6) δ : 1.28 (9H, s), 2·40 (3Η, s), 3.76 (2Η 'd), 5.66 (2Η, s) , 6.16 (1Η,

S 119 201111360 t), 6.41 (1H, s), 6.72 (1H, dd), 7 34 η u ΊΛΊ (^ } Λ 34〇Η·(1)&gt;7.38(2Ηί d), 7.47 (2H ' m), 7·57 (1H, # » 7 ηττ 7.63-7.66 (2H, with m straight), 7.83 (1H ' dd), 7.96 (1H, h, 〇a R1〇rm ,, d) ' 8.09 (1H,d ), 8.18 (1H, d), 8.81 (1H, br s), 9 】 WltT (lH, brs) 〇) 9.l5 (lH, brs), 10_43 t two = example 3_ (3_ third butyl small P-toluene core than saliva = "yloxy ~" ("oxygenamine

DIPEA

OMe

Example 15

^Including intermediate G1 (35 mg, 62 micromoles) and deleting A (43 3 μl two 248 mM) in anhydrous THF (25 liters) in a solution of 2 甲Oxyacetamidine chloride (17 () microliters, move millimolar) The reaction mixture is evasive for 15 minutes and then warmed up to 1.75 hours after the dish, the shai reaction is added to the 丨% NR The feed was taken in ME(R) (10 mL) and the resulting mixture was maintained at room temperature for 1 hour and then evaporated in vacuo. The residue was subjected to scx capture and release and the crude product thus obtained was subjected to flash column chromatography (Si 〇 2 ' 12 g, containing [5% MEOH in ETOAC] in iso-firing] 25-100 %, gradient elution) was purified to give the title compound as a beige solid (14 mg, 34° /.), Example 15; Rt 2.28 min (method 2); M/Z 636 (M+H)+ (ES+) ; lH NMR (400MHZ, DMSO-d6) δ : 1.28 (9H,S), 2.40 (3H,S), 120 201111360 3.30 (3H,S),3.82 (2H,S),3.90 (2H,D),6.41 (1H, S), 6.72 (1H, DD), 7.33 (1H, D), 7.38 (2H, D), 7.47 (2H, M), 7.57 (2H, Μ), 7·64 (1H, m ) ' 7.83 (ih, DD), 7.92 (1H, T), 7.96 (1H, 〇) ' 8.09 (1H, D), 8 2 〇 (1H, D) ' 8.82 (1H, br S), 9.14 (1H , br S), 1〇59 (m, br S). Example 16: N-(2-(4-(4-(3-(3-Terbutylbutyl-7-p-tolyl_m_〇tb 嗤_5_yl))yl)naphthalenyloxy)» Specific biting &gt; 2_ylamino) 2 decylethyl) tetrahydro-2-indole-pyranyl-4-pyramine

Me Example 16 Into a suspension of tetrahydro-2H-pentanyl carboxylic acid (34.6 mg, 〇266 mmol) in anhydrous DCM (3.0 mL) l, 0.310 millimoles) then add i drops dmf. The reaction mixture was maintained at 0. (: for 2 minutes and then warmed to room temperature. After 1 hour, the mixture was cooled to hydrazine. Add intermediate G1 (50 mg '0.089 mmol) and DIpEA (77 〇Π microliter, 0.444 m) Moore) and the resulting mixture was stored in 〇 it for % minutes and then warmed to room temperature for h5 hours. The reaction was added to a solution containing 1% NH3 in MeOH (3.0 mL) and quenched and produced The mixture was maintained at room temperature for 3 minutes and then evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product thus obtained was subjected to 121 201111360 flash tube chromatography (si 〇 2 ' 12 g Purify to give the title compound as a beige solid (18 mg, 29%), EtOAc (EtOAc: EtOAc: EtOAc 2) ; m/z 676 (M+H)+ (ES+) ; lH NMR (400MHz, DMSO-d6) δ : 1.28 (9H, s), 1.54 (4H, m), 2.40-2.42 (4H, with m Overlap), 3.27 (2H, dt), 3.83 (4H, m), 6.41 (1H, s), 6.71 (1H, dd), 7.33 (1H 'd), 7.38 (2H, d), 7.47 (2H, m ), 7.56-7.64 (3H, Overlap with m), 7·83 (1H, dd), 7.96 (1H, d), 8.02 (1H, t), 8.09 (1H, d), 8.99 (1H, d), 8.82 (1H, br s), 9.14 (1H, br s), 10.54 (1H, br s). Example 17: N-(2-(4-(4-(3-(3-tert-butyl-1-p-tolyl-lH-n) Bisazo-5-yl)ureido)naphthalen-1-yloxy)acridin-2-ylamino)-2-ketoethyl)

Adding isonicotine hydrogen in the solution of intermediate G1 (50 mg, 89 mmol) and DIPEA (77 μL, 444 mmol) in anhydrous THF (2.5 liters) under 〇C nitrogen. Chloride (47 4 mg, 266 mmol) and the reaction mixture was maintained in hydrazine for 15 minutes and then at room temperature for 1.5 hours. The reaction was quenched by the addition of aq. EtOAc (3 mL MeOH) (3 mL) and the mixture was then allowed to stand at room temperature for 45 min and then evaporated in vacuo. The residue was subjected to sCX capture 122 201111360. The crude product thus obtained was obtained by flash tube chromatography (Si 〇 2, 12 g, containing [5% MeOH in EtOAc] in isohexane. Purification by 50-100% (gradient elution) afforded compound (31 mg, 52%) as a beige solid, Example 17; Rt 2.17 min (method 2); m/z 669 (M+H)+ (ES+ 1h NMR (400MHz, DMSO-d6) δ : 1·28 (9H, s), 2·39 (3H, s), 4·09 (2H, dd), 6.39 (1Η, s), 6.74 (1Η) , dd), 7.33 (1Η, d), 7.36 (2H 'd), 7.46 (2H, m), 7.56-7.63 (3H, overlap with m), 7.75 (2H, dd), 7.83 (1H, dd), 7.95 (1H,d), 8.07 (1H, d) ' 8.21 (1H,d), 8.72 (2H,dd),8.80 (1H,br s),9.05 (1H,br s),9.12 (1H,br s ), 10.72 (1H, br s). Example 18: N-(4-(4-(3-(3-t-butyl-p-p-tolyl)-ih-pyrazol-5-yl))-naphthalenyloxy)D-pyridyl-2_ Base)_2_(2_(methylsulfonyl)ethylamino)acetamide

In a solution containing 2-(indolyl hydrazino)acetic acid (33.1 mg, 240 mmol) in anhydrous DCM (3.0 mL), EtOAc EtOAc EtOAc. _1_ene-1-amine (31.7 microliters, 24 Torr) and the reaction mixture was maintained at room temperature for 5 hours. The resulting mixture was added to a solution containing Intermediate G1 (45 mg, 80 mmol) and DIPEA (55.6 μL, 319 mmol) in dry DCM (2 mL) The combined reaction mixture was maintained in hydrazine. (: up to 3 minutes

S 123 201111360 and then at room temperature for 2 hours. The reaction was quenched by adding a solution of 1% NH3 in MeOH (3 mL) and the resulting mixture was maintained at room temperature for 1 hour and then evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product thus obtained was purified by flash column chromatography (Si.sub.2, 12 g, containing [5% MeOH in EtOAc] % 'gradient elution> was purified and then purified using ethyl acetate to give the title compound (7 mg, 12%) as a pale brown solid, Example 18; Rt 2.21 min (method 2); m/z 684 (M+ H)+ (ES+); lH NMR (400MHz, DMSO-d6) δ: 1.29 (9H, s), 2.40 (3H, s), 3.08 (3H, s), 3.98 (2H, d), 4.14 (2H, s), 6.41 (1H, s), 6, 75 (1H, dd), 7.34 (1H, d), 7.38 (2H, d) ' 7.47 (2H ' m), 7.57 (2h, m), 7.64 (1H , m), 7.83 (1H, dd) ' 7.96 (1H, d), 8.09 (1H, d), 8.21 (1H, d), 8.55 (lH't), 8.79 (lH'brs), 9.12 (lH, Brs), 10.65 (1H, br s) ° Example 19: N-(2-(4-(4-(3-(3-tert-butyl-1-p-tolyl-lH-nb 唆-5-yl) Glycosyl)naphthalenyl-l-oxyl p-pyridyl-2-ylamino)_2-ketoethyl)-3-morpholine-propionamide

Add a solution of 3-norfosyl propionate (33 9 mg, 213 mmol) in anhydrous DCM (3.0 mL) with hydrazine under nitrogen (21.0 μl '248 mmol) Ears, followed by the addition of 1 drop of DMF and the 124 201111360 reaction mixture was maintained at 〇t:i4 for 2 minutes and at room temperature for 25 hours. The mixture was cooled to 〇r and intermediate G1 (4 mM, 71 mM) and DIPEA (61.8 dl, 355 mM) were added and the combined reaction mixture was held for 3 min and then At room temperature for 2.25 hours. The reaction was quenched by the addition of 1% aq. The residue was subjected to scx capture and release and the crude product thus obtained was purified by flash column chromatography (Si 2 , 12 g, containing [5% MeOH in EtOAc] Purified by 〇/〇, gradient elution, then EtOAc / EtOAc EtOAc (EtOAc) m/z 705 (M+H)+ (ES+) ; lH NMR (400MHz, DMSO-d6) 6 : 1·29 (9H, s), 2.29 (2H 't), 2.33 (4H, m), 2.40 (3H, s), 2.47 (2H, m), 3.52 (4H, t), 3.87 (2H, d), 6.40 (1H, s), 6.72 (1H, dd), 7.33 (1H, d) , 7.37 (2H, d), 7.47 (2H, m), 7.57-7.64 (3H, overlap with m), 7.83 (lH, dd), 7.96 (lH, d), 8.09 (1H, d), 8.19 (1H , d), 8.22 (1H, t), 8.85 (1H, br s), 9-16 (1H, br s), 10.48 (1H, br s). Example 20: N-(2-(4-(4-(3-(3-tert-butyl-1-yl-p-tolyl-1H-pyrazol-5-yl))))]naphthalenyloxy)) Bipyridin-2-ylamino)-2-ketoethyl)

125 S 201111360

Intermediate G1

DIPEA

Example 20 To a solution of the intermediate Gl (45 mg, 80 mmol) and DIPEA (48.7 μl of '279 house Mo) in anhydrous THF (3.0 mL) Gas (22 9 liters, 2 Torr) and the reaction mixture was maintained at 2 () minutes and then at room temperature for 2.5 hours. The reaction was quenched by the addition of 1% aq. The residue was subjected to scx capture and release and the crude product thus obtained was subjected to flash column chromatography (Si 〇 2 ' 12 g, containing [5% MeOH in EtOAc] in a different appearance] 40-100 %, gradient elution) was purified and then milled with isohexane/Et〇Ac (2:1 v/v). The material was extracted into EtOAc (m.sub.2), EtOAc (EtOAc) Rt 2.24 minutes (method 2); m/z 677 (M+H)+ (ES+); 1h NMR (400MHz, DMSO-d6) δ: 1.29 (9H, s), 2.40 (3H, s), 3.24 ( 4H, t), 3.52 (4H, t), 3.77 (2H, d) ' 6.41 (1H, s), 6.72 (1H, dd), 6.83 (1H, t), 7.32 (1H, d) ' 7.38 (2H , d), 7.47 (2H, m), 7.58 (2H, m), 7.64 (1H, m), 7.83 (1H, dd), 7.96 (1H, d), 8.09 (1H, d), 8.19 (1H, d), 8.79 (1H, br s) ' 9.12 (1H, br s), 10.39 (1H, br s). 126 201111360 2,6--fluoro-3-(2-(2-methoxyethoxy)ethoxy)benzoic acid

For a period of 1 hour under nitrogen at 〇 ° C under a solution of 2,4-difluorobenzene (11.0 g, 85 mmol) and mpEA (15.5 mL '89 mmol) in DCM (150 mL) MOM-Br (7.33 mL, 89 mp) was added and the reaction mixture was then maintained at room temperature for a period of hr. The resulting mixture was washed successively with water, 2M aqueous NaOH solution, water and brine, and then dried (MgSO.sub.4) and evaporated in vacuo to give 2,4-difluoro-1-(methoxy methoxy) as a colorless oil. Base) benzene (Π.7 g '88% yield). Rt 3.17 minutes (method 1, basic, no ionization observed) was used directly in the next step (see below). In a solution containing 2,4-difluoro-1-(decyloxydecyloxy)benzene (2.00 g, 11.5 mmol) in THF (30 mL) A solution containing n-butyllithium in hexane (1.4 M, 8.20 mL ' 11.48 mmol) was added dropwise. The mixture was stirred at -7 ° C for 1.5 hours and then poured onto freshly pulverized dry ice (~2 gram). Once the foaming disappeared, the mixture was warmed to room temperature and water (20 mL) was added. The aqueous solution was extracted twice with ether and then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting suspension was subjected to sonication for 5 minutes and then extracted twice with DCM and the combined DCM extracts were dried (MgSO.sub.4) and evaporated in vacuo. The residue was triturated with a mixture of isohexane and ether (50: 3 vol/vol) to give a white solid.

S 127 201111360 2,6-monofluoro-3-(methoxyoxyloxy) oxanoic acid (199 g, 77% yield); Rt 2.31 min (basic method 1); m/z 219 (10)+), It is used directly in the next step (see below). TMS-C1 (7.94 ml, was added dropwise to a solution containing 2,6-difluoro-3-(methoxymethoxy)benzoic acid (2.74 g, 12.6 mmol) in MeOH (50 mL) 62.8 millimoles) and the resulting colorless solution was heated back to %il for 3 hours. The resulting mixture was cooled to room temperature and then evaporated in vacuo and the residue was taken and taken to give &lt;RTI ID=0.0&gt;%); Rt 2.29 minutes (basic method υ ; m/z 187 (m_h)_ (ES-). Will contain 2,6-difluoro-3-hydroxybenzoic acid decyl ester (5 〇〇 mg, 2 66 毫a mixture of monoethylene glycol mono-ether ether (479 mg, 3.99 mmol) and PPh3 (1046 mg '3.99 mmol) in THF (12.0 mL) was purged with nitrogen 'cooled to -78 ° C And then DIAD (753 μl ' 3.99 mmol) was added over a period of 5 minutes. The reaction mixture was warmed to room temperature and after 1 h, aqueous NaOH (2M, 10 mL) and water (10 mL) The mixture was stirred rapidly for 1 hour at room temperature. The resulting mixture was extracted with ether (50 liters) and the organic layer was back-extracted with aqueous NaOH (1M, 20 mL). The ether is extracted twice and then acidified to pH 1 by the addition of concentrated hydrogen acid and the mixture is extracted three times with ether. The combined extracts are dried (MgS〇 4) and evaporating in vacuo to give the compound (0.51 g, 65%) as a white solid, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 21 · Ν·(2·(4·(4-(3-(3-Terbutyl butyl-p-phenyl)-1-pyridyl-5-yl)-ureido)naphthalene-I-yloxy)pyridine _2-aminoaminoketoethyl)-2,6-difluoro-3-(2-(2,oxyethoxy)ethoxy)benzamide

MeO, &lt;y

Intermediate G1

EDC, DMAP fBu

Example 21

MeO,

NH

Containing 2,6-difluoro-3-(2-(2-decyloxyethoxy)ethoxy) benzoic acid (29.4 mg, 1 〇 6 mmol), intermediate G1 (5 g , 89 mM) and EDC.HC1 (22.1 mg, 115 mmol) in anhydrous DCM (4 mL) in EtOAc. DMAp (i 6 gram, 0.013 Torr) was added under nitrogen and the reaction mixture was maintained at room temperature for 24 hours. The resulting mixture was distributed between saturated aqueous NaHC 3 (15 liters) and DCM (15 mL). The aqueous layer was separated and extracted with DCM (15 mL) and the combined organic extracts were washed with brine (2 liters) and then dried (MgS 〇 4) and evaporated in vacuo. The residue was eluted by flash column chromatography (Si 2 , 12 g, containing [5% MeOH in EtOAc] in isohexane, eluting with 20-80% gradient and then Si 〇 2 ' 12 g </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; (M+H)+ (ES+); lH NMR (400MHz, DMSO-d6) δ ·· 1.28 (9H, s),

129 S 201111360 2.39 (3H, s), 3.23 (3H, s) ' 3.44 (2H, m), 3.58 (2H, m) ' 3.73 (2H, m) ' 4.10 (2H 'd), 4.16 (2H, m ), 6 4〇(1H ' s),6·69 (1H ' dd) ' 7.06 (1H,dt), 7.26 (1H,dt), 7.34 (1H,d),7.37 (2H,d),7.47 ( 2H,m), 7.57 (1H, m), 7.63-7.65 (2H' overlaps with m)' 7.84 (1H, dd), 7.95 (1H, d), 8.09 (1H, d), 8.20 (1H 'd) , 8·85 (m, br s), 8 95 (1H, t), 9.17 (1H, br s), 10.60 (iH, br s). Still other examples of the present disclosure are prepared by reacting intermediate pj with intermediate C or intermediate D. ^

Intermediate HI: Ν-(4-(4-Aminophenoxy)pyridine_2-yl)_2-methoxyethylamine

US PatAppI 2008319188; Prt^ u |~~ Υ = Ν02 Production Example 53 ^ M2 IY = nh2; Intermediate H1 containing 4-(4-nitrophenoxy)acridin-2-amine [US Patent Application 2008319188, Manufacture Example 53] (〇.60 g, 2.60 mmol of DIPEA (0.680 μl, 3.89 Torr) in DCM (15 mL) was added dropwise at 〇 ° C under nitrogen for 5 min. _Methoxyethyl chloroform (225 μl, 3.89 mmol). Maintain the reaction at room temperature for I6 hours and add 1% bribe 3 solution of Me〇H (10 ml) 130 201111360 cold. The mixture was evaporated in vacuo and EtOAc (EtOAc)EtOAc. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut (4_Acidylphenoxy) ° pyridine-2-yl)acetamide (0.73 g, 92%);

Rt 1.88 minutes (method 2); m/z 304 (M+H)+ (ES+). Will contain 2-decyloxy-indole-(4-(4-nitrophenoxy)acridin-2-yl)acetamide (730 mg, 2.41 mmol) in MeOH containing AcOH (5 drops) / The solution in DCM (1: i volume/volume, 8 〇 ml) was hydrogenated by the Thales H-cube (1. 〇ml min q, room temperature '70 mm 1〇% pt/c Cat-Cart , full hydrogen mode) and then evaporated in vacuum. The residue was partitioned between DCM (20 mL) and sat. NaHC.sub.3 (1 mL). The organic phase was washed with brine (2 mL) EtOAc (EtOAc m. ; m/z 274 (M+H)+ (ES+). Example 22: Ν·(4-(4_(3-(3-Tertibutyl-i-p-tolyl-1H-pyrazol-5-yl)ureido)phenoxy)pyridine-2_yl)_2 _methoxyacetamide

3-tert-Butyl-1-p-tolyl·1Η_σ-biazole-5-amine (21〇 mg, 0.915 mmol) was added in three portions to CDI (0.148 g, 0.915 m)

131 S 201111360 Moor) was suspended in DCM (5.0 mL) and the mixture was maintained at room temperature for 16 h. A solution containing intermediate H1 (6 mg, 22 mmol) in DCM (0.6 mL) was added and a second portion of intermediate H1 (7.5 g, 28 m. ) iDCM (0.075 ml). The reaction was quenched with MeOH (10 mL) EtOAc. The residue was partitioned between EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by flash chromatography (EtOAc EtOAc (EtOAc) , 86%), Example 22; Rt 2.40 min (method 2); m/z 529 (M+H)+ (ES+); lH NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.37 ( 3H, s), 3.33 (3H, s), 4.01 (2H, s), 6.36 (1H, s), 6.66 (1H, dd), 7·10 (2H, d), 7·35 (2H, d), 7.39 (2H, d), 7.50 (2H, d), 7.61 (1H, m), 8.17 (1H, d), 8.37 (1H, s), 9·14 (1H, s), 10.03 (1H , s). Intermediate H2: N-(4-(4-Amino-2-methylphenoxy)acridin-2-yl)-2-methoxyacetamide

W02007059257 ^ |-Υ=Ν02 Y = NH2; Intermediate H2 contains 4-(2-methyl-4-nitrophenoxy)acridin-2-amine [W02007059257] (405 mg, 1.65 m) at 〇 °C To a suspension of THF (5.0 132 201111360 ml) was added 2-methoxyacetamidine (604 μL, 6.61 mmol) and DIPEA (1.44 mL, 8.26 mmol) and The reaction mixture was warmed to room temperature for 30 minutes. The reaction was quenched by addition of 1% aq. A second portion of a solution containing NH3 in MeOH (7M, EtOAc) was then evaporated and evaporated. The residue was subjected to SCX capture and release to give 2-methoxy-N-(4-(2-methyl-4-nitrophenoxy)pyridine-2-yl)acetamide as an orange oil ( 357 mg, 92% purity '63%); Rt 2.07 min (method 2), m/z 318 (M+H) + (ES+), which was used directly in the next step (see below). Will contain 2-methoxy-N-(4-(2-methyl-4-nitrophenoxy)n than bit-2-yl)acetamide (357 g, estimated purity 92%, 1.04 m Mole) A solution of a mixture of MeOH (20 mL) and AcOH (2.0 mL) was hydrogenated by EtOAc (1.0 mL. min -1,25T, 55 mm 10% Pt/C Cat- Cart, all hydrogen mode) and then evaporated in vacuum. The residue was extracted into a mixture of MeOH (20 mL) and AcOH (2 mL) and under the same flow conditions, at the ascending temperature (1.0 ml min -1,40 ° C, 55 mm 〇% Pt/C Cat -Cart, full hydrogen mode) re-hydrogenation. The mixture was concentrated in vacuo to give the title compound as a viscous liquid, Intermediate H2; &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&& It is used directly in the next step (see below). 133 1 201111360 Example 23: N-(4-(4-(3-(3-t-butyl-p-p-tolyl)-X-pyrene-5-yl))-methylphenoxy )»»比比特-2-yl)-2-methoxyacetamide Me

To a solution containing CDI (0.811 g, 5.00 mmol) in DCM (10 mL) was added dropwise at room temperature with 3-tert-butyl-indole-p-phenyl-1H-pyrazole-5- A solution of the amine (1.15 g '5.00 mmol) in DCM (10 mL). A whole portion of this solution (7.0 mL) was added to a pre-prepared intermediate H2 sample containing DCM (5.0 mL) and the reaction mixture was maintained at room temperature for 16 hours. The resulting reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si.sub.2, 12 g, containing 1 / 〇 [1% NH3 in MeOH] in DCM. Purified to give the title compound as a yellow solid (54 mg, 10% for the second phase), Example 23; Rt 2·52 min (method 2); m/z 543 (M+H)+ ( ES+) ; lH NMR (400MHz ' DMSO-d6) δ : 1.28 (9Η, s), 2.06 (3Η, s), 2.38 (3Η, s), 3·33 (3Η, s), 4.01 (2H, s) , 6.36 (1H, s), 6.60 (1H, dd), 7.01 (1H, d), 7.29 (1H, dd), 7·34 (2H, d), 7.40 (2H, d), 7.44 (1H, d ), 7.54 (1H, d), 8.16 (1H, d), 8.36 (1H, s), 9.07 (1H, s), 9.98 (1H, s). Intermediate H3 : N-(4-(4•Amino-3-methyl phenyloxy-2-pyridin-2-yl)-2-methoxyacetamide 134 201111360

F

NO:

To a solution of 2-aminopyridine-4-ol (355 mg, 3.22 mmol) in DMF (4 mL). Hydrogenated steel (6 〇 0 / 分散 dispersed in mineral oil, 193 mg, 4.83 mmol) was added portionwise under nitrogen and the reaction mixture was warmed to room temperature for 2 hours. The mixture was cooled down and a solution containing .4-fluoro-2-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in DMF (2.0 mL) was added dropwise and the mixture was warmed to room Wenda is 16 hours. The resulting mixture was diluted with water (20 mL) andEtOAc. The combined organic extracts were washed with brine (20 mL) then dried (MgSO.sub.4) and evaporated in vacuo and the residue was purified by flash column chromatography (Si 〇2, 4 g, Purification with 25% EtOAc in EtOAc (EtOAc (EtOAc) Rt 1.2 〇 min (method 2); m/z 246 (M+H) + (ES+). Containing 4-(3-mercapto-4-nitrophenoxy)acridin-2-amine (300 mg, 1.22 mmol) in THF (5.0 mL) and DIPEA (1.7 mL, 6.12 mmol) In the suspension, 2-methoxyethane gas (447 μL, 4.89 mmol) was metered in a single batch at 〇 ° C and the reaction mixture was warmed to room temperature for 30 minutes. A solution containing NH3 in MeOH (7M, 3.0 mL) was added and the mixture was evaporated in vacuo. Disperse the residue in DCM (50 ml) and water (40 ml)

135 S 201111360 and the organic phase is separated from the sister (MgS04) and evaporated in a vacuum. The residue was purified by flash tube chromatography (Si2, 40 g, 5% MeOH in DCM elute elute (4-(3-Methyl-4-nitrophenoxy)α-pyridin-2-yl)acetamide (210 mg, 53%); 1^2.06 min (method 2); m/z 318 ( M+H)+ (ES+). Will contain 2-methoxy-N-(4-(3-indolyl-4-nitrophenoxy)acridin-2-yl)acetamide (208 mg, 0.656 mmol) in MeOH ( A solution of a mixture of 10.0 ml) and AcOH (0.5 ml) was hydrogenated by a Taylors H-cube (1.0 ml·min-1, 4 Torr. 〇, 55 mm 10% Pt/C Cat-Cart, all The title compound (192 mg '97%), intermediate H3; Rt I.I9 min (method 2); m/z 288 (M+H)+ (ES+); It is used directly in the next step (see below). Example 24: N-(4-(4-(3-(3-t-butyl-p-p-tolyl_m-0)-yl) glysyl)-3-mercaptophenoxy)acridin-2-yl) -2-methoxyacetamide tDf«

In a suspension containing CDI (811 mg ' 5.00 mmol) in DCM (1 mL), add 3 - tert-butyl 丨 对 _ p-tolyl. ] 47 g, 5 〇〇亳 mol) in dcm (1 〇〇 milli solution and the reaction mixture was maintained at room temperature for 16 hours. I was injured. The solution (1·34 ml) was added dropwise to the middle. (192 136 201111360 g '0.668 mmol) in DCM (3.0 mL) and the combined reaction mixture was maintained at room temperature for 30 min and then treated with Me 〇H (1.0 mL). The reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (40 g, MeOH in EtOAc EtOAc Solid target compound (145 mg, 38%), Example 24;

Rt 2.48 minutes (method 2); m/z 543 (M+H)+ (ES+); 1h NMR (400MHz, DMS〇-d6) δ: 1.27 (9H 's), 2.19 (3H, s), 2.38 ( 3H ' s) ' 3.33 (3H, s), 4·02 (2H, s), 6.36 (1H, s) ' 6.66 (1H, dd) ' 6.96 (1H, dd), 7.03 (1H, d), 7.34 (2H ' d) ' 7.42 (2H,d) ' 7·63 (1H,d),7.81 (1H,d), 8.18 (1H 'd),8·29 (1H,s) ' 8.73 (1H,s ), 10.03 (1H, s).

Intermediate H4: N-(4-(4•Amino-2-methoxyphenoxy)pyridine·2-yl)-2-methoxyethenylamine OH

H2i I—y = no2 ° Y = NH2; Intermediate Η4 in a suspension of 2-amino-based bite _4·alcohol (0.251 g, 2 28 mmol) in MeCN (4. mM) Add the surface (423 μl, 2.8 〇 millimolar) and add the oxa 2_:oxy-4-nitrobenzene (3 〇〇mg, 丄·75 mmol) to the mixture after 3 〇 A solution of DMF (2.0 liters). The reaction mixture is maintained at room temperature for up to several hours and

S 137 201111360 and then heated to 80 ° C for 16 hours. After cooling to room temperature water (2.0 mL) was added and the mixture was evaporated in vacuo. The residue was partitioned between DCM (3 mL) and brine (20 mL) and the organic layer was partitioned and dried (MgS s 4) and evaporated in vacuo. The residue was purified by flash column chromatography (40 mL, EtOAc (EtOAc) -Methoxy-4-nitrophenoxy)pyridine-2-amine (234 mg, 50 〇/〇); Rt 1.25 min (Method 2); m/z 262 (M+H)+ (ES+). Containing 4-(2-methoxy-4-nitrophenoxy) D-pyridin-2-amine (233 mg '0.892 mmol) in THF (5.0 mL) and DIPEA (775 μL, 6.12 m In the suspension of Moer), in the sputum. 2 Add 2-methoxymethoxyethane (325 μl, 3.57 mmol) in a single batch. The reaction mixture was warmed to room temperature for 1 hour and then a solution of NH3 in MeOH (7M &lt The mixture was evaporated in vacuo <RTI ID=0.0>: </RTI> <RTIgt; The organic phase was separated and dried (MgSOS 4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si.sub.2, 4 g, eluting with 2% MeOH in DCM, eluent) to afford 2-methoxy- N-(4-(2-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide (234 mg, 78%); Rt 1.89 min (Method 2); m/z 334 ( M+H)+ (ES+). Will contain 2-decyloxy-N-(4-(2-methoxy-4-nitrophenoxy)π-pyridin-2-yl)ethenol (232 g, 696 mmol) a solution containing a mixture of MeOH (30 liters) and AcOH (2.0 liters) by Tyre

13S 201111360 Stefan-cube is hydrogenated (10 ml min-1,5 〇ΐ, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and then evaporated in vacuo to give the title compound as an impure oily liquid. Intermediate

Rt 1.08 minutes (method 2); m/z 304 (M+H)+ (ES+). The material containing residual acetic acid was used in the next step without further purification (see below). Example 25: N-(4-(4-(3-(3-Terbutyl-1-)-p-tolyl-111-oxazol-5-yl)ureido)-2-nonyloxyphenoxy) Pyridine_2_yl)_2_methoxyethenamine

Me Example 25 In a suspension containing CDI (17.2 g, 106 mmol) in DCM (15 mL), add 3 g portions of the third butyl-1-pair at room temperature over 40 minutes. Phenyl-1H-pyrazole-5-amine (24.4 g, 1 〇 6 mmol) and the reaction mixture was stirred at room temperature for 2 h. An aliquot of this / gluten solution (1.39 ml) was added dropwise to a mixture of the intermediate H4 obtained in DCM (3.0 ml) and the mixture was maintained at room temperature for 16 hours. The reaction mixture was quenched with MeOH (EtOAc)EtOAc. The residue was purified by flash column chromatography (EtOAc EtOAc EtOAc (EtOAc) '64%) 'Example 25; Rt2 42 minutes (method 2); m/z 559 (M+H)+ (ES+); 1H NMR (4〇〇MHz, s 139 201111360 s〇-d6) δ · 1.28 ( 9H,S), 2.38 (3H,s),3.33 (3H, .69 (3H 's),4 〇〇(2H,s),6 37 (1Ή,s),6 % (iH, ' 6·94 (1H ' dd) ' 7.07 (1H,d), 7.35 (2H,d),7 .7 42 and m heavy),7·52 (1H,d),8.12 (1H , d), 8.36 (1H, S ' 9.17 (1H, s) ' 9.94 (1H, s). Between, body H5 : Ν·(4·(4·amino·2,3_dimercaptophenoxy) hexane-2-yl) -2_methoxy ethoxylated ΟΗ ^

Y = N〇2 Y = nh2; Intermediate H5 匚 contains t-amine. Add dbU (570 micron) to the suspension of liter of N (4.0 ml) in liters of N (4.0 ml) at room temperature. 3.78 millimoles) and after 30 minutes, a solution containing fluinol, 3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The reaction mixture was maintained at room temperature for 16 hours; DMF (2.0 mL) was added and the mixture was taken to heat (10). ◦ 且 and (10) cooled to room temperature for 64 hours. The resulting mixture was evaporated in vacuo and the residue was partitioned between DCM (5 mL) and brine (3 liters). The organic layer was separated and dried (MgSOS 4) and evaporated in vacuo. The residue was subjected to flash column chromatography (Si 〇 2, 4 〇 / g, EtOAc in isohexane, 20-100%, eluted with gradient and then S 〇 2 ' 12 g, containing 50% EtOAc In isohexane, isocratic elution) was purified to give 4_(2,3-dimethyl-7-nitrobenzene 140 201111360 oxy) mouth-yellow-nose 17 mg, 19%) as a yellow solid; Rt 147 minutes (method 2 broad m/z 260 (M+H) + (ES+). Contains 4-(a 2,3-diindenyl 1 nitrophenoxy)-deno-2 〇1〇 mg' 〇 .424 *Moule) in a suspension containing DIPEA (37 μL, 2.u mmol) in THF (3.0 mL), in a single batch, 2·methoxy oxime ( 155 microliters, 丨7() millimolar). The reaction mixture was warmed to room temperature for i hr and a solution containing &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The residue was distributed between dcm (50 liters) and brine (40 mL) and the organic phase was separated and dried (MgS 〇 4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si 〇 2 '40 g, containing 20-50% EtOAc in isohexane, gradient washed k) -(2,3-Dimethyl-4-succinylphenoxy)acridin-2-yl)-2-decyloxyacetamide (94 mg, 67%), Rt 2.14 min (Method 2); m/z 332 (M+H)+ (ES+). Ν-(4-(2,3-monomethyl-4-nitrophenoxy) η 咬 _ _ _2 ( ( 90 (90 mg, 0.272 mmol) in MeOH A solution of a mixture of (30 ml) and AcOH (2.0 ml) was hydrogenated by Thales H-cube (1. 〇ml. min-1, 50 °C '55 mm 10%) Pt/C Cat-Cart, full hydrogen mode) and then evaporated in vacuo to give the title compound (82 mg, 100%), Intermediate H5; nt L21 min (method 2); m/z 302 (M+H) + (ES+).

S 141 201111360 Example 26: N-(4-(4-(3-(3-tert-butyl-p-tolyl_m-pyrazol-5-yl)))-2,3-dimethylphenyloxy Pyridine: base): methoxy B

Add 1 gram portion of tert-butyl-1-p-phenyl-1H-pyrazole to a suspension containing CDI (17.2 g, 1 〇6 mmol) in DcM (150 mL) over 40 min. 5-amine (24.3 g, 1 〇 6 mmol) and the mixture was stirred at room temperature for 2 h. A solution of the intermediate D3 (0.54 ml) was added dropwise to a solution of Intermediate H5 (82 mg, s 272 mM) in DCM (2.0 mL). A second portion (〇.54 mmol) of the intermediate D3 solution was added after 40 minutes and a third portion (0.2 mL) was added over 2 hours and the resulting mixture was maintained at room temperature for 16 hours. The reaction was quenched with MeOH (2 mL) and EtOAc. The residue was purified by flash column chromatography (40 g, EtOAc (EtOAc: EtOAc) 〇mg, 72%), Example 26; Rt 2.50 min (method 2); m/z 557 (M+H)+ (ES+); lHNMR (400 MHz, pMSO-d6) δ: 1.27 (9H, s), 2.03 (3H, s), 2.13 (3H, s), 2.38 (3H, s), 3.33 (3H, s), 4.01 (2H, s), 6.34 (1H, s) ' 6.56 (1H ' dd) ' 6.92 ( (1H, d) (1H, s), 9.99 (1H, s). Intermediate H6: N-(H4_Aminomethoxyphenoxy)pyridin-2-yl)-2-methoxyacetamide

' nH2; Intermediate H6 was added DBU (661 μL, 438 mmol) to a suspension of 2·Aminopyridine 4·ol (483 mg, 4.38 mmol) in MeCN (2.0 mL) and The reaction mixture was maintained at room temperature until a homogeneous solution was formed. At this time, force was added to 1-fluoro-3-indolyl-4-nitrobenzene (5 g, 2.92 mmol). The reaction mixture was maintained at room temperature for 5 hours and heated to 80. (: </ RTI> </ RTI> EtOAc (20 mL) and water (2 mL) The aqueous layer was separated and extracted with EtOAc (20 mL). EtOAc (EtOAc) Chromatography, 40 g, EtOAc (EtOAc: EtOAc:EtOAc _2_amine (420 mg, 55%); Rt uo min (method 2); m/z 262 (M+H)+ (ES+). 143 201111360 Contains 4-(3-methoxy-4-nitrophenoxy)π-pyridin-2-amine (420 mg '1.61 mmol) in DIPEA (562 μL, 3.22 mmol) In a suspension of DCM (4.0 mL), at 0. 2- Add 2-methoxy bethane (220 μl, 2.41 mmol) in a single batch. The reaction mixture was warmed to room temperature for 1 h and then a solution containing &lt;RTI ID=0.0&gt;&gt; The resulting mixture was maintained at room temperature for 30 minutes, evaporated in vacuo and residue was partitioned between DCM (5 <RTIgt; The organic phase was separated and evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc, EtOAc, EtOAc EtOAc 2-methoxy_N_(4-(3-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide (401 mg, 75%) as a pale yellow oil; Rt 1.87 min (Method 2); m/z 334 (M+H)+ (ES+). 2-曱-oxy-N-(4-(3-decyloxy-4-nitrophenoxy)acridin-2-yl)acetamide (400 mg, 1.2 〇 mmol) is contained A solution of a mixture of DCM (5.0 liters), MeOH ' (5.0 mL) and Ac 〇h (0.5 mL) was hydrogenated by the ssssssssssssssssssssssssssss Mm 1〇% Pt/C Cat-Cart, full hydrogen mode) and then evaporated in vacuo to give the title compound, intermediate H6; Rt 1.1 min (method 2); m/z 304 (M+H)+ ( ES+). This sample containing residual acetic acid was used in the next step (see below) without further purification. 144 201111360

Intermediate H6

Intermediate D3

Example 27 is 106 millimoles) in dcm (10) ml) AT: 丄A rn〇 minutes added 1 gram portion of 3_t-butyl + p-methyl-based-1H•钵5-amine (24 4 g, (10) Millions) and the mixture was allowed to stand at room temperature for 2 hours. A solution of the intermediate D3 (5.0 ml) was added dropwise to a mixture of the crude crystals of the previous intermediates in DCM (2.0 ml) and the mixture was maintained at room temperature. The reaction mixture was quenched with EtOAc (EtOAc EtOAc (EtOAc) elute elute It is purified in iso-burning, 〇_ι〇〇%, gradient elution). The crude product thus obtained was taken into a mixture of DCM (2·············· The supernatant was decanted and the solid was dried <RTI ID=0.0>: </RTI> to EtOAc (m. H)+ (ES+) ; lH NMR (400MHz, DMS0-d6, 100 °C) δ : 1.24 (9H ' s), 2.38 (3H, s), 3.40 (3H, s), 3.84 (3H, s), 4.01 (2H ' s), 6.31 (1H, s), 6.67 (1H, m), 6.69 (1H, d) ' 6.86 (1H,d) ' 7·31 (2H ' s 145 201111360 d), 7.39 (2H,d), 7.65 (1H,d), 8.06 (1H,d) ' 8.17 (1H, d), 8.30 (1H, s), 8.70 (1H, s) and 9.47 (1H, s). Other examples of the present disclosure are derived by reacting intermediate A with an isocyanate or an amine ruthenium chloride. Alternatively, the intermediate A is converted to a compound represented by the intermediate J, which is then reacted with an amine.

Example 28: N-Ethyl-N'-4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-indazol-5-yl)ureido)naphthalen-1-yl Oxy) oxidin-2-ylurea 146 201111360

EtNCO tBu

Intermediate A

Example 28

In the solution of 3 intermediate A (53 g, read millimolar) in anhydrous (. liter ml), add human isocyanate (2) under e nitrogen, liter: 0.26 mil (iv) and (four) minutes later The reaction mixture was returned to the room temperature for 45 hours. The mixture was cooled to hydrazine and a second portion of ethyl isocyanate (21 liters, 0.26 mmol) was added and the resulting mixture was warmed to room temperature after 2 s. Further, the second reaction was carried out as follows. In a solution containing Intermediate A (50 mg, 0.099 mmol) in anhydrous pyridine (2 mL) Ethyl isocyanate (23 μl '0.30 mmol) was added dropwise under nitrogen and the reaction mixture was slowly warmed to room temperature. After 48 hours, a second portion of ethyl isocyanate (23 μL, 〇·29 mmol) was added. After a further 3 hours, the reaction mixture was quenched with EtOAc EtOAc (EtOAc) The crude residue was combined and purified by flash column chromatography (EtOAc, EtOAc (EtOAc: EtOAc) The title compound was obtained as a white solid (29 mg, 25%), mp.: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1.03 (3H, t), 1.28 (9H, s), 2.40 (3H, s), 3.08-3.14 (2H, m), 6.41 (1H, s), 6.55 (1H, dd), 6.91 (1H, d) , 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, 147 s 201111360 d) ' 7.55-7.59 (1H, m), 7.63_7.67 (m, m), 7 82 (lH, dd ), 7.89-7.99 (2H, m), 8.06 (m, d), 8 〇 9 (m, sentence, 8.78 (1H, s)' 9.02 (1H, s), 9.12 (m, s). Example 29: 4-(4-(3-(3-tert-butyl-[p-tolyl-this]-pyranyl-&amp;-)-ureido)naphthalen-1-yloxy)-pyridin-2-ylurea

Intermediate A CI3C person NC0 2.NH,

Example 29 To a solution of intermediate A (50 mg, 〇〇99 mmol) in anhydrous hydrazine (1.5 ml) under nitrogen and tris-ethyl isocyanate (15 μl '0.12 Torr) and After 3 minutes, the reaction mixture was warmed to /jm. After 24 hours, an additional portion of tri-ethylene acetyl isocyanate (29 μL, 0.25 mmol) was added and after 42 hours the reaction was added to a solution containing 1% NH3 in MeOH (2.0 ML) is quenched. After a further 30 minutes, the resulting mixture was evaporated in EtOAc (EtOAc m. 〇_750/0, Gradient elution) was purified to give the title compound as a white solid (7 mg, 13%) </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; + (ES+) ; lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 2.40 (3H, s), 6.41 (1H, s), ό.52 (1H, dd), 6.95 (1H,d),7.31 (1H,d),7.37 (2H,d),7.45-7.47 148 201111360 (2H ' m) ' 7.54-7.61 (1H,m),7.62-7.67 (1H,m),7 83 (1H ' dd) ' 7.95 (1H ' d) ' 8.06 (1H,d) ' 8,09 (1H,d), 8.81 (1H ' s),9.03 (1H,s),9.15 (1H,s) . Example 30: N-propan-2-yl-N,-4-(4-(3-(3-tert-butyl)-p-tolyl-1Η-β-pyran-5-yl)ureido) naphthalene Baseoxy) bite_2_base pulse

丨 PrNCO

Intermediate A -- ' Example 30 Add 2-Isocyanogen-propanil (68 μl, 〇691) to a solution containing intermediate A (70 mg, 〇·138 mmol) in pyridine (ι $ 耄) Its molar) and an additional portion of 2-isocyanoindole di-burn (68 μl '0.69 mmol) was added at room temperature after 24 hours. After 72 hours, the hydrazine reaction was quenched by the addition of 1% hydrazine in MeOH (2.0 liters) and the mixture was evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc, EtOAc (EtOAc) eluting The subject compound (32 mg, 39%), Example 30: Rt 5.47 min (Basic Method 1); m/z 592 (M+H)+ (ES+); lH NMR (400 MHz, DMSO-d6) δ ppm 1.08 (6H,d), 1.28 (9H, s), 2.40 (3H, s), 3.69-3.77 (1H, m)' 6.41 (1H, s), 6.55 (1H, dd), 6.94 (1H, d), 7.31 (1H, d), 7.38 (2H, d), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H, t) ' 7.78 (1H, br d), 7.82 (1H, d), 7.96 (1H,d),8.05-8.09 149 201111360 (2H 'overlap with m), 8.78 (1H,s) ' 8.94 (1H,s),9 12 (1H, Example 31: 1-(3-(third Butyl)-1-(p-phenyl)-m•carbazole_5yl)_3_(4-((2_(3-phenylureido)))

Add phenyl isocyanate (75 μL, 0 691 mmol) to a solution containing intermediate A (70 mg, 0.138 mmol) in „bite (15 ml) and react 16 hours later. The mixture was quenched by adding 1% NH3 in Me〇H (2.0 mL). After another 3 min, the resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si. 2 '12 g, MeOH in DCM, EtOAc (EtOAc) elute elute elute 5.70 minutes (basic method 1); m/z 626 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (9Η, s), 2.40 (3Η, s), 6.42 ( 1H ' s), 6·65 (1H, dd), 6.98 - 7.03 (2H, with m vertical) ' 7.28 (2H, m)' 7.34-7.39 (3H, overlap with m), 7.44-7.48 (4H ' Overlap with m), 7 59 (1H, t), 7.66 (1H, t), 7.84 (1H, d), 7·98 (1H, d), 8·10 (1H, d), 8.17 (1H, d ),8·79 (1H, s) ' 9.14 (1H ' s) ' 9.33 (1H, s), 10.41 (1H, s) 150 201111360 Example 32 : 1-(4 _((2-(3·indolyl)pyridinyl)oxy)vaporation_work (second butyl) small (p-phenyl)_1Η-η than sal _5_yl)

Benzyl isocyanate (85 μL, 〇·69 ΐ millimolar) was added to a solution of Intermediate A (70 mg, 0.138 mmol) in pyridine (15 mL). The reaction mixture was quenched by adding a solution of 1% NH3 in MeOH (2-0 mL). After 3 min, the resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography ( Si 〇 2, 12 g, MeOH (MeOH) eluted elute elut elut elut elut elut elut elut elut elut Rt 5.64 min (basic method l); m/z 640 (M+H)+ (ES+); iHNMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 2.40 (3H, s), 4.33 ( 2H, d), 6.41 (1H, s), 6.57 (1H, dd), 6.93 (1H, s), 7.21-7.27 (3H, overlap with m) ' 7.30_7.32 (3H, m), 7.37 (2H , d), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H, t), 7.83 (1H, d), 7.96 (1H, d), 8.06-8.09 (2H, overlap with m), 8.45 (1H, br, s), 8.77 (1H, s), 9.12 (1H, s), 9.18 (1H, s). 151 201111360

Add cyclopropyl isocyanate (57.4 mg, 〇691 mmol) to a solution of the intermediate containing AW, 0.138 mM in a bite (5 ml) and maintain the mixture at room temperature for 64 hours. . The reaction was quenched by the addition of EtOAc (1 mL) and evaporated and evaporated. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) elute elut elut elut elut elut elut elut The subject compound (11 mg, 13%), Example 33: Rt 5.47 min (Basic Method 1); m/z 590 (M+H)+ (ES+); 1HNMR (400 MHz, DMSO-d6) δ ppm 0.36- 0.40 (2H,m),0.59-0.63 (2H,m),1.28 (9H,s),2.40 (3H ' s) ' 2.52 (1H ' m), 6.41 (1H,s),6.57 (1H ' dd) , 6.97 (1H, br s), 7.31 (1H 'd), 7.38 (2H, d), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H 't), 7.81 (1H, d), 7.92 (1H, br s), 7.96 (1H, d) ' 8.04-8.10 (2H, overlap with m), 8.78 (1H's)' 8.96 (1H's)' 9.12 (1H, s). 152 201111360 Example 34: 1-(3-(Third butyl)-1-(p-tolyl)-1Η_η than saliva &amp; base)_3-(4-((2-(3-(2-(2-methoxy)) Ethyl ethyl) ketone).

Add 1-isocyanoguanidino-2-methoxyethene (no mg, 0.138 mmol) to a solution of intermediate A (70 mg '0.138 mmol) in acridine (15 mL) The mixture was maintained at room temperature for 64 hours. The reaction was quenched by MeOH (1.0 mL) and evaporated. The residue was purified by flash column chromatography (Si 〇 2 ' 12 g, MeOH in DCM, 0-5 〇 / 〇, gradient elution) and then triturated from MeOH. The title compound (27 mg, 32%), m.p. 1.28 (9H, s), 2.40 (3H, s), 3.23-3.27 (5H, m), 3.33-3.36 (2H, m), 6.41 (1H, s), 6.56 (1H, dd), 6.94 (1H, s), 7·31 (1H, d), 7.38 (2H, d), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H, t), 7.82 (1H, d), 7.96 (1H , d), 8.03 (1H, br s), 8.05-8.09 (2H, overlap with m), 8.78 (1H, s), 9.10 (1H, s), 9.12 (1H, s). Example 35: 1-(3-(Third-butyl) small (p-tolylbisazol-5-yl)-3-(4-((2-(3-cyclopentyl)))) -yl)oxy)naphthalen-1-yl)urea

153 S 201111360

Intermediate A ^y^Hco tBu

Example 35 Add cyclopentanyl isocyanate (78 μl, 0.691 mmol) to a solution of intermediate A (7 mg, 0.138 mmol) in hydrazine (1.5 mL) and maintain the mixture The room temperature is up to Μ hours. An additional portion of cyclopentyl isocyanate (78 microliters of '0-691 millimolar) was added and after an additional 24 hours the reaction mixture was quenched by adding hydrazine-containing NH3MMe(R) (2 mL). After 30 minutes, the resulting mixture was evaporated in vacuo and residue was purified by flash column chromatography (EtOAc, EtOAc (EtOAc) Purified and then triturated from acetone to give the title compound (17 mg, 20%), mp. lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 1.28-1.38 (2H, m), 1.49-1.64 (4H, m), 1.77-1.85 (2H, m), 2.40 (3H, s), 3.88-3.93 (1H, m), 6.41 (1H, s), 6.55 (1H, dd), 6.95 (1H, d), 7.31 (1H, d), 7.38 (2H, d) ' 7.46 (2H , d), 7.57 (1H, t), 7.65 (1H, t), 7.82 (1H, d), 7.89 (1H, br s), 7.96 (1H, d), 8.05-8.10 (2H, and m Overlap), 8.78 (1H, s), 8.92 (1H, s), 9.12 (1H, s). 154 201111360 Example 36: 1-(3-(Tert-butyl)-1-(p-tolyloxazol-5-yl)-3-(4-((2-(3-methyl)ureido)pyridine-4 -yl)oxy)tea small base) gland

Add guanidinium isocyanate (50 μL, 〇8〇6 mmol) to a solution containing Intermediate A (50 mg, 〇·〇99亳 丨 丨 吼 吼 丨丨〇) The mixture was maintained at room temperature for 24 hours. An additional portion of isocyanate vinegar (150 μl '0.26 mmol) and π ratio tr (〇5 mL) were weighed in and the reaction mixture was maintained at room temperature for 96 hours and then distributed to DCM. Between (30 ml) and saturated aqueous NaHC〇3 (10 ml). The aqueous layer was separated and extracted with DCM (10 mL). The residue was purified by flash column chromatography (EtOAc EtOAc EtOAc (EtOAc) 21%), Example 36: Rt 5.24 min (basic method 1); m/z 564 (M+H)+ (ES+); lH NMR (400 MHz, DMS 〇-d6) δ ppm lH NMR (400 MHz, DMSO -d6) δ ppm 1·28 (9H, s) ' 2·39 (3H, s), 2·65 (3H, d), 6.40 (1H, s), 6.54 (1H, dd), 6.87 (1H, d), 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, m), 7.58 (1H, m), 7.64 (1H, m), 7.81 (1H 'd), 7.88 (1H, br s), 7.95 (1H, d), 8.05 (1H, d), 155 s 201111360 8.08 (1H, d), 8.76 (1H, s), 9.09 (1H, s), 9.11 (1H, s ). Example 37: 2-(3-(4_((4-(3)-(3-(t-butyl))-1-(p-tolyl)-1H.β)pyran-5-yl)glycosyl)naphthalene-1- Ethyl)oxy)indol-2-yl)

To a solution of intermediate A (200 mg, 0.395 mmol) in pyridine (15 liters) was added 2-isocyanoguanidinoacetate (135 μL, 丨18 耄mol) and the mixture Maintain at room temperature for 16 hours. The reaction was quenched by MeOH (2OmL) and the mixture was evaporated. Toluene (in liters) was added and the mixture was again evaporated in a vacuum. The crude product thus obtained is used

Me 〇 H (10 mL) gave the title compound as a white solid (16 </ RTI> </ RTI> </ RTI> 61%), Example 37: Rt 2.47 min (method 2); m/z 636 (M+H)+ (ES+) ; 1H NMR (働MHz, DMS〇d6) δ ppm 1.18 (3H ' t) ' 1.28 (9H, s), 2.4G (3H, s), 3.90 (2H, br s) ' 7.33 (1H ' d), 7·38 (2H,d), 7.46 (2H,d),7.57

s), 9.33 (1H, s). d) ' 4.08 (2H ' q), 6.41 (ih, s), 6 59 (m, (10), 6 88 (m, 156 201111360 Example 38: 4-(3-(4-(4-(3-(3) -T-butyl-p-p-tolyl-1H d 嗤-s-yl)-yl)naphthalen-1-yloxy)anthracene 2-yl)-based hexahydro-n-pyridyl ratio

Add benzyl 4-isocyanohydrazinium hexahydropyridinecarboxylate (154 mg, 0.592 mmol) to a solution of intermediate A (100 g, 0.197 mmol) in pyridine (2 mL) Suspension of pyridine (ίο ml) = and the mixture was maintained at room temperature for 48 hours. The second portion of 4 isocyaninyl hexahydropyridine-1-carboxylic acid benzyl ester (102 mg, 0.394 mmol) was added and the mixture was evaporated in vacuo. The residue was extracted with MeOH and the alcoholic extract was evaporated in vacuo to give a residue, which was purified by flash column chromatography (Si. 5%, gradient elution) was purified and then recrystallized from MeOH to give N-pyryl carbazate as a pale pink solid: 4-(3-(4-((4-(3-) 3-(t-butyl)-1-(p-phenyl)-im°--5-yl)-yl)naphthalen-1-yl)oxyl sigma-denyl-2-yl)dehydro)hexahydro Benzyl pyridine-1-carboxylate (R = CBz) (25 mg, 16%): Rt 5.72 min (Basic Method 1); m/z 768 (M+H)+ (ES+); 1HNMR (400 MHz, DMSO -d6) δ ppm 1.24-1.32 (11H, m), 1.78-1.81 (2H, m), 2.40 (3H, s), 3.03 (2H, br s), 3.67 (1H, br 157 s 201111360 s) ' 3.81 -3.84 (2H,m),5.06 (2H,s),6.41 (1H,s), 6.57 (1H ' dd) ' 6.94 (1H,s), 7.30-7.39 (8H,m),7.46 (2H 'd ), 7.57 (1H 't), 7.65 (1H, t), 7.81 (1H, d), 7.96 (2H 'd) ' 8.06-8.09 (2H, m), 8.77 (1H, s), 8.99 (1H, s), 9·12 (1H, s) 含有 containing the N-benzyl urethane (15 mg, 0.196 制备) prepared before In a solution of acetic acid (5 mL), HBr (45% solution in AcOH, 248 μL, 1.956 mmol) was added to 〇〇c and the reaction mixture was warmed to room temperature. After that, the reaction mixture was diluted with MeCN (3.0 mL) and purified by SCX capture and elution. The crude product thus obtained was purified by flash column chromatography (Si〇2, containing [5% MeOH The title compound (100 mg, 8 %) was obtained as a white solid (yield: EtOAc) m/z 633 (M+H)+ (ES+) ; lH NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (2H, m), 1.29 (9H, s), 1.70-1.74 (2H, m) , 2.40 (3H, s), 2.42-2.50 (3H, m), 2.84-2.88 (2H, m), 3.50 (1H, br s), 6.41 (1H, s), 6.56 (1H, dd), 6.95 ( 1H, br s), 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, d), 7·57 (1H, t) ' 7·65 (1H, t), 7.82 (1H, d ), 7.87 (1H, br s), 7.96 (1H 'd), 8.05-8.10 (2H, m), 8.79 (1H, br s), 8.94 (1H 's), 9.13 (1H, s). 158 201111360 Example 39: N_Ethyl 4_(3_(4_(4 yl))yl)naphthalenyloxy)di=

Contains Example 38 (30 mg, 47 亳 Mo

Microliter '95 millimoles) in DCM n 、,) and DIPEA (16.5 ~ Guandou) in a solution of ULM (1.0 liters), in (TC: milk containing bismuth (7) microliters' A solution of 57 millimolars in dcm (〇5 liter) and the reaction mixture was warmed to room temperature for up to hr. An additional portion of acetonitrile (2 〇 liters, 28 mM) was added to DCM (0.3 mL) and saturated aqueous NaHc 〇 3 (2.0 mL) was then added and the reaction mixture was passed Separate and filter. The organic phase was evaporated in vacuo and the residue was purified by flash column chromatography (Si2, 5% MeOH in EtOAc) Purified to give the title compound (25 g, 76%), m. , DMSO-d6) δ ppm 1.13-1.40 (11H, m), 1.70-1.84 (2H, m), 1.98 (3H, s), 2.40 (3H, s), 2.81 (1H, t), 3.14 (1H, t), 3.66-3.71 (2H, m), 4.06-4.09 (1H, m), 6.41 (1H, s), 6.57 (1H, dd), 6.94 (1H, br s), 7.31 (1H, d), 7.37 (2H,d), 7.46 (2H,d), 7.57 (1H,t), 7.65 (1H,t), 201111360^2/^'),7'97(2^'),8·06-8 ·^ b ) ' 9·00 (1H, s), 9, 14 (1H, s). Example 40: 2_(2-methoxyethoxy) small (4_(3,_(yl-p-tolyl-1H-pyrazol-5-yl)ureido))-yl)ureido) Hydrogen acridine small base)

CI

Example 38

MeO 〇-

DIPHA tBuν&gt;ΜτΟΟ〇Λγ:

Example 40 —C0^

Adding 2_(2-methoxyethoxy)acetamidine at 〇0C in a solution containing Example 38 (20 mg, 32 亳 MOF '63 mmol) in DCM, υ耄 )) A solution of chlorine (7 2 g, 4::, ear) in DCM (0.5 mL) was then warmed to room temperature for one hour. An additional portion of 2-(2-methoxyethoxy)acetamidine (3.5 mg, 24 mmol) was added to DCM (3 mL) and sat. aqueous NaHC. 2.0 ml) was added and the reaction mixture was filtered through separate phases. The organic phase was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc EtOAc EtOAc EtOAc

Purified and then captured by SCX to give the title compound (8.4 mg, 32%) as an off-white solid, Example 40: Rt 5.18 min (Basic Method 1); m/z 749 (M+H)+ (ES+ ; iH NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.41 (11H, m), 1.78-1.82 (2H, m), 2.40 (3H, s), 2.84 (1H, t), 3.10 (1H, 160 201111360 t), 3.24 (3H, s), 3.45-3.46 (2H, m), 3.53-3.55 (2H, m), 3.65-3.72 (2H, m), 4.04-4.17 (3H, m), 6.41 ( 1H, s), 6.58 (1H, dd), 6.95 (1H, s), 7.31 (1H, d), 7.37 (2H, d) ' 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H , t), 7.82 (1H, d), 7.96 (2H, d), 8.05-8.10 (2H, m), 8'79 (1H, s), 8.99 (1H, s), 9.13 (1H, s). Example 41: N-methylsulfonyl 4-(3-(4-(4-(3-(3-tert-butyl-l-p-tolyl-1Η-»-bazin-5-yl))) Naphthyl-i-yloxy)acridin-2-yl)ureido)hexahydropyridyl

In a solution containing Example 38 (40 mg, 63 mmol) and DIPEA (22.0 μl, 126 mM) in DCM (1.溶液 A solution of methanesulfonyl vapor (5.9 μL, 76 mmol) in DCM (0.5 mL) was added under nitrogen. The reaction mixture was warmed to room temperature and an additional portion of decanesulfonium chloride (2.0 liters, 28 mM) was added to DCM (0.3 mL). After 1 h, the reaction mixture was washed with saturated aqueous NaHC EtOAc (EtOAc). The organic phase was evaporated and the residue was purified by flash column chromatography (EtOAc, EtOAc (EtOAc: EtOAc) Purification afforded the title compound as a sm. (28 mg &lt;RTI ID=0.0&gt;&gt;&gt;&&&&&&&&&&&&&&&&& 〇MHz, DMSO-d6) δ PPm 161 201111360 1·29 (9H, s), 1.40-1.48 (2H, m), 1.87-1.91 (2H, m), 2.40 (3H, s), 2.84-2.92 (5H , m), 3.37-3.47 (2H, m), 3.60 (1H, br s), 6.41 (1H, s), 6.57 (1H, dd), 6.96 (1H, br s), 7.31 (1H, d), 7.37 (2H,d), 7.46 (2H,d), 7.57 (1H,t), 7.65 (1H,t),7.82 (1H,d),7.96 (1H,d), 8.00 (1H,br s), 8.07-8.10 (2H, m), 8.80 (1H, s), 9.01 (1H, s), 9.14 (1H, s) 〇 Example 42: N-(4-(4-(3-(3•3rd) -1 -p-tolyl_m-pyrazol-5-yl)-yl)naphthalen-1-yloxy)°biti-2-yl)fosfene-4-treazone

In a solution containing intermediate A (50 mg, 0.099 mmol) and DIPEA (52 μl, 0.30 mmol) in anhydrous beta ratio (1.5 ml), add blush to 〇 ° C under nitrogen咁-4-carbon helium (14 μl, 0.12 mmol). The reaction mixture was maintained at 〇 ° C for 15 minutes, warmed to 40 ° C for 4 hours and then left at room temperature for 20 hours. The reaction mixture was again heated to 40 ° C for 3 hours and then quenched by the addition of 1% NH3 in MeOH (2 mL). After 45 minutes, the resulting mixture was evaporated in vacuo and the residue was purified by flash chromatography eluting EtOAc (EtOAc (EtOAc) -80% 'gradient elution> was purified to give the title compound as a beige powder. Example 42 (16 mg, 25%): Rt 2.18 min (Method 162 201111360 2); m/z 620 (M+H)+ ( ES+) ; lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H 's), 2.40 (3H, s), 3.36 (4H, t), 3.53 (4H, t), 6.41 (1H, s), 6.61 (1H, dd), 7.31 (1H, d) ' 7.34-7.41 (3H, m), 7.46 (2H 'd), 7.55-7.59 (1H, m), 7.63-7.68 (1H, m), 7.84 ( 1H, dd), 7.96 (1H, d), 8.08 (1H 'd) ' 8.11 (1H, d), 8.80 (1H, s), 9.13 (1H, s), 9.25 (1H, s). Example 43: N-(4-((4-(3-(3-(t-butyl))-l-(p-tolylpyrazol-5-yl))-yl)-naphthalenyl)-oxy)pyridinyl 2-yl)-4-methylhexahydropyrrol-1-carboxamide

Add 4-mercaptohexahydropyrazole-1-carbon to a solution containing intermediate A (70 mg, 0.138 mmol) and dipea (120 μl '0.691 mmol) in anhydrous pyridin (1.5 mL) Chlorohydrochloride (138 mg, 〇 691 mmol) was maintained and the mixture was maintained at room temperature for 64 hours. The reaction was quenched by adding 1% aq. EtOAc (MeOH) (EtOAc) The organic solution was washed with water and brine and dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si 〇 2, containing [7% NH3 in MeOH] in DCM, 〇 5%, </ RTI> 163 201111360). Solid target compound (28 mg, 31%), mp. 1.28 (9H, s), 2· 15 (3H, s), 2.23 (4H, t), 2.40 (3H, s), 3.37 (4H, t), 6.41 (1H, s), 6.58 (1H, dd) , 6.95 (1H, d), 7.31 (1H 'd), 7.38 (2H, d), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H, t), 7.84 (1H, d), 7.95 (1H, d), 8.07-8.11 (2H 'm), 8.79 (1H, s), 9.12 (1H, s), 9·19 (1H, s). Example 44: 3-(4-((4-(3-(3-(tert-butyl))-1-(p-tolyl)-1 Η-oxazol-5-yl)-yl)naphthalene-1- ))oxy) 〇 than bite _2·yl)-1,1-dimethyl detachment

Add dimethylaminocarbazide (18 μm) to a solution containing intermediate A (50 mg, 0.099 mmol) and DIPEA (34 μl '0.20 mmol) in anhydrous lJ (15 ml)升, 〇. 20 mmol, and the reaction mixture was maintained at room temperature for 64 hours. The reaction was quenched by adding EtOAc (MeOH) (EtOAc) The residue was subjected to flash column chromatography (Si 〇 2 ' 12 g, MeOH in DCM, 0-5% gradient elution; then Si 〇 2, 4 g, containing [5% MeOH in Purified by EtOAc <RTIgt; </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; /z 578 (M+H)+ (ES+) ; lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 2.40 (3H, s), 2.86 (6H, s), 6.41 (1H, s), 6.67 (1H, br s), 7.32 (2H, d), 7.37 (2H, d), 7·47 (2H, d), 7.58 (1H, t), 7.65 (1H, t), 7.84 ( 1H, d), 7.97 (1H, d), 8.09-8.13 (2H, m), 8.82 (1H, s), 9.00 (1H, br s), 9.15 (1H, s) 〇 Example 45: Ν_( 4-((4-(3·(3_(T-butyl)-1-(p-tolyl)_m_ 0 峻 -6-5-yl) yl)-naphthalen-1-yl)oxy) 吼-2 -based) hexahydro b

Deaf

Intermediate A - containing intermediate A (130 mg, 0.257 mmol) and mpEA (134 μl, 0.770 mmol) in anhydrous. To the solution of the bite (2 liters), hexahydroindole-1-carbochloro (64 μL, 0.51 mmol) was added and the mixture was maintained at room temperature for 64 hours. % ΝΗ3 was quenched in MeOH (2. <RTI ID=0.0></RTI> MeOH). The residue was separated by flash column chromatography (Si 〇 2, 12 g, MeOH in DCM, 0-5%, eluted and then SiO 2 , 12 g, Et0Ac in isohexane,

40-100/〇' gradient elution followed by si〇2, 12 g, containing MeOH in DCM, 0-3%, gradient elution) was purified and finally captured by scx

S 165 201111360 The compound was obtained as a pink solid (30 mg, 18%). Example 45: Rt 5.40 min (Basic Method 1); m/z 618 (M+H)+ (ES+); lH NMR ( 400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 1.39-1.42 (4H, m), 1.44-1.54 (2H, m), 2,40 (3H, s), 3.33-3.36 (4H, m ), 6.41 (1H, s), 6.74 (1H, br s), 7.31 (1H, d), 7.35 (1H, br s), 7.37 (2H, d), 7.46 (2H 'd), 7·57 ( 1H, t), 7.65 (1H, t), 7.85 (1H, d), 7.96 (1H, d), 8.07-8.11 (2H, m), 8.80 (1H, s), 9·13 (2H, s) . Intermediate J: prop-1-en-2-yl 4-(4-(3-(3-tert-butyl-1_p-tolyl-1Η-° than sal-5-yl))-naphthalene- 1-yloxy)π ratio biting ·2·ylaminocarboxylic acid brewing

In a solution containing intermediate A (50 mg, 〇_〇 99 mmol) and hydrazine-hydrazinoporphyrin (13 μL, 0.12 mmol) in THF (2.0 mL) - at -78 ° C A solution containing propylene-1-en-2-yl sulphate (13 μL, 0.12 mmol) in THF (2 mL) was added dropwise. Upon completion of the addition, the mixture was warmed to room temperature and after 72 hours the reaction was quenched by adding 1% NH3 in MeOH (1 mL). After 1 hour, the resulting mixture was evaporated in vacuo. The whole (7 ()%) of the residual money was purified by flash column color layer 166 201111360 separation method (Si02 '4 g, containing EtOAc in isohexane, 〇_5〇%, gradient elution) The title compound (21 mg, 50%), mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Example 46: N-Mercapto-N-(2-(norfosin-4-yl)ethyl)_ν,-4_(4·(3_(3_Tert-butyl-1-p-tolyl-1Η- Pyrazol-5-yl)ureido)naphthyloxy) 0 to bite-2-yl gland

Example 46 Addition of N-methyl-2- to a solution of intermediate J (50 mg, 85 mmol) and carbaryl 4 (1.0 μL, 9 mmol) in THF (5 mL) Ethylamine (12. 2 mg, 85 mmol) and the reaction mixture was heated to 55 °C for 16 hours. The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si.sub.2, 4 g, containing Me0H in DCM, 〇1〇0/〇, gradient elution and then Si〇2 4 g of vermiculite containing MeOH in DCM, 0-5%, gradient eluting then EtOAc (2 g, EtOAc (EtOAc) Compound (15 mg '25%) 'Example 46: Rt 1.90 min (Method 2); m/z 677 (M+H)+ (ES+); lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 2.39 (3H, s), 2.46 (6H, overlap with m, part 167 s 201111360 copies obscured by DMSO signal), 2.81 (3H, s), 3 33 (2H, m, partially obscured by H20 peak) , 3.6? (4H, m), 6 4〇 (ih, d (IH'dd), 7.29 (1H, d), 7.32 (1H, d), 7 37 (2H, d), 7.46 (2H, d) , 7.56 (1H ' m) ' 7.64 (1H, m), 7 83 (m, d), 7.95 (1H 'd), 8.06-8.10 (2H 'overlap with m), 8 78 (m, s), 9.10 (1H 's), 10.42 (1H, br s). Example 47: N-(4-(morpholine-4-yl)butyl-oxime, -4·(4 (3 (3•3 butyl) -1-p-tolyl-1Η“比嗤-5-yl” Yl) yloxy ^ + walled veins group -2_

Example 47 Adding a heart-free solution to a solution containing intermediate J (50 mg, 853⁄4 mol) and a group of methyl morphine (1.0 μl, 9 mmol) in THF (5 ml) 1-amine (13.4 mg, 0.085 mmol) and the reaction mixture was heated to 55. (: 16 hours. The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si s, 4 g, MeOH in DCM, 0-10% gradient elution) The compound (15 mg, 25%) was obtained as a purple solid, mp (1,4 g, EtOAc) Method 2); m/z 691 (M+H)+ (ES+): lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 168 201111360 1.38_1·44 (4H 'overlap with m) ' 2 23 (2H, called, 2 29 (4H, overlap with m)' 2.39 (3H ' s), 3.08 (2H, m), 3.53 (4H, m) 6.40 (1H, s)' 6.55 (1H, dd ), 6.90 (1H, d), 7.30 (1H, d) ' 7.37 (2H ' d) ' 7.46 (2H,d),7 56 (m,叫,7 64 (lH, m)'7.81(1H'd ), 7.95(lH'd)'7.96(1H,brs)'8.05 (1H,d) ' 8.07 (1H,d),8.77 (1H,s),9."(1H,s), 9.11 (1H, s). Example 48. N-(2-(Isofosin-4-yl)ethyl)N, o-(tetra)-tert-butyl-1~p-phenylphenyl-1HK5-yl)ureido) Base-wide ratio 唆-2- base pulse

Me Example 48 Add 2_ 福福代代 to a solution containing intermediate J (50 mg, 85 胄mol) and N-methylfoazole (1.0 μl of '9 mmol) in (5 mM) 6 amine (11·〇 microliters '9〇胄 mol) and the reaction mixture was heated to 55 ° C for 16 hours. The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si2, 4 g, MeOH in DC1V [2- 2-5%, gradient elution) The title compound was obtained as a purple solid (15 mg, 26%), mp.: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; +H)+ (ES+) ; lH NMR (400 MHz, DMSO-d6) at l〇〇°C δρριη 1.31 (9H, s), 2.39 (3H, s), 169 s 201111360 2.75 (~6H ' br s, Partially obscured by HOD signal), 3.37 (2H, br s), 3.69 (4H ' br s) ' 6.34 (1H, s), 6.56 (1H, dd), 6.99 (1H 'd), 7·23 (1H , d), 7.33 (2H, d), 7.46 (2H, d) ' 7.55 (1H ' m), 7.61 (1H, m), 7.86 (1H, d), 7.87 (1H, d) ' 8.04 (1H, Br s), 8.07 (1H, d), 8.11 (ih, d), 8.55 (1H, br s), 8.90 (1H, br s), 8.93 (1H, br s). Example 49: N-(3-methylisoxazole-5-yl)f-based Ν, _4_(4·(3_(3^ dibutyl-1-p-tolyl-111-° than 嗤-5- (base)) 蒸-) 蒸-1-yloxy) π than 唆-2-yl gland

Add (3_ mercaptoisoxazole) to a solution of intermediate J (50 mg, 85 mmol) and Ν-methylmorpholine (1.0 μL, 9 mmol) in THF (5.0 mL) 5-Methylamine (9.5 mg, 85 mmol) and the reaction mixture was heated to 55 ° C for 16 h. The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc EtOAc Compound (16 mg, 28%), mp. Ppm 1.27 (9H, s), 2.16 (3H, s), 2.39 (3H, s), 4.44 (2H, d), 6.13 (1H, s), 6.40 (1H, s), 6·59 (1H, dd ),6·88 (1H,d),7.31 (1H, 170 201111360 d) ' 7.36 (2H,d), 7.45 (2H,d),7.56 (1H,m),7 64 (1H, m) ' 7.81 (1H,d),7.95 (1H,d) ' 8.〇6〇〇(2H, overlap with m), 8.54 (1H,br s) ' 8.77 (1H ' s) ' 9 12 (m,'s) , 9.27 (1H, s). Example 50: N-(l-fluorenyl)hexahydropyridine_4_yl-v, _4·(4_(3·(3_t-butyl-1-p-tolyl-1Η-η than salivation_5_) Substrate

Example 50 Adds methylhexahydropyridine to a solution of intermediate J (50 mg, 85 4 moles) and N. methylmorpholine (1.0 μL, 9 mmol) in THF (5 mL) 4-amine (9.7 mg, 85 mmol) and the reaction mixture was heated to 55 ° C for 16 h. The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc EtOAc EtOAc EtOAc Compound (19 mg, 34%) as a purple solid, Example 50: Rt 1.96 min (Method 2); m/z 647 (M+H)+ (ES+): 1HNMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 1.36 (2H, m), 1.75 (2H, m), 2.00 (2H, m), 2.13 (3H, s), 2·39 (3H, s), 2·57 (2H, m), 3.43 (1H, s), 6.40 (1H ' s), 6.56 (1H, dd), 6.94 (1H, d), 7.30 (1H, d), 7_37 (2H, d), 7.46 (2H, 171 S: 201111360 d) ' 7.56 (1H,m) ' 7.64 (1H ' m), 7.81 (1H ' d), 7.89 (1H ' brs) '7.95 (lH'd), 8.06-8.10 (2H, overlapping with m ), 8.77 (1H, s), 8.96 (1H, s), 9.11 (1H, s). Example 51: N-(4-(4-(3-(3-tert-butyl)-p-tolyl-1H-0 ratio _5-yl) glandyl)naphthalen-1-yloxy)β ratio Pyridyl)_4-finchylhexahydropyridine-1-carboxyguanamine

Add hexahydropyridine to a solution containing intermediate J (50 mg, % 亳mol) and Ν-曱 吗 福 0 0 (1.0 μl, 9 mmol) in Ding (5. 4-alcohol (8.6 mg, 85 mmol) and the reaction mixture was heated to 55 C for 16 hours. The resulting mixture was evaporated in vacuo and residue was purified by flash column chromatography (Si 〇 2 ' 4 g, MeOH containing EtOAc (EtOAc EtOAc)

Rt 2.05 min (method 2); m/z 634 (M+H)+ (ES+): 1h NMR (400 MHz, DMSO-d6) δ ppm 1.27 (9H, s), 1.24 (2H, m), 1_65 ( 2H ' m), 2·39 (3H, s), 2·99 (2H, m), 3, 57 (1H, m), 3.74 (2H ' m) ' 4.64 (1H, d), 6.40 (1H, s), 6.57 (1H, dd) ' 7.29 (1H, d), 7.32 - 7.37 (3H, overlap with m), 7.45 (2H, d), 7.56 (1H, m), 7.63 (1H, m), 7.84 (1H,d), 7.94 (1H, 172 201111360 d), 8.06-8.10 (2H' overlaps with m), 8 77 (1H, s), 9.10 (1H, s), 9.13 (1H, s). Example 52: N-(3-(isoxazolyl)propyl)k(4_(3-(3_t-butyl•1-p-phenylene-1H-pyrazole·5·yl)ureido)naphthalene ^-oxy)pyridine-2-based gland

Add 3-(1Η-imidazol-1-yl) to a solution of intermediate J (50 mg of '85 mM Mo) and methyl phoxim (1.0 liter of '9 house Mo) in THF (5.0 mL) Prop-1-amine (ι〇·6 mg, 85 mmol) and the reaction mixture was heated to 55 °C for 16 hours. The resulting mixture was evaporated in vacuo and the residue was purified by flash column chromatography (Si. , 12 g, containing 4% [1% NH3 in MeOH] in EtOAc (EtOAc) elute elute elute Method 1); m/z 658 (M+H)+ (ES+): lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 1.85 (2H, m), 2.39 (3H, s) , 3.06 (2H, m), 3.95 (2H, m), 6.40 (1H, s), 6.56 (1H, dd), 6.86 (1H, t), 6.89 (1H, d), 7.16 (1H 't), 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, d), 7.57 (1H, m), 7.60 (1H, 173 s 201111360 t), 7.64 (1H, m), 7.81 (1H, d ), 7.95 (1H 'd) ' 8.06-8.10 (3H, overlap with m), 8.77 (1H, s), 9.07 (1H, s), 9.12 (1H, s) o Example 53: N-(2-( 3-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-<b-azol-5-yl)))-naphthalenyloxy)) Gland) ethinyl) tetrahydro

Add 2-amino-1 in a solution of intermediate J (50 mg, 85 mmol) and N-mercaptophyrin (1.0 μL, 9 mmol) in THF (5 mL) (tetrahydropyrrol-1-yl)ethanone hydrogenate (14 mg, 85 mmol) and DIPEA (14.0 μL, 85 mmol) and the reaction mixture was heated to 55 C for 20 hours. The resulting mixture was heat-generated in a vacuum and the residue was eluted by flash column chromatography (Si 2 , 12 g, containing 2% [1% NH3 in MeOH] in DCM. Purified to give the title compound as a purple solid ( 丨 9 mg, 32%) </RTI> </ RTI> </ RTI> </ RTI> Rt 2.19 min (method 2); m/z 661 (M+H) + (ES+): 1h NMR (400 MHz ' DMSO-d6) δ ppm 1.28 (9H ' s), 1.75 (2H, m), 1.86 (2H, m), 2.39 (3H, s), 3.29 (2H, m), 3.35 (2H, m), 3.88 ( (2H, d) 7.56 (1H, m), 7.64 (1H, m), 7.82 (1H, d), 7.95 (1H, d), 8.06-8.10 (2H, overlap with m), 8.14 (1H, br s), 8.77 (1H , s), 9.1 1 (1H, s), 9·29 (1H, s).

Other examples of the present disclosure are derived via an alternative synthetic method in which 4-(4-1 schwitzina-1 -yloxy) is converted to phenylcarbamate and The reaction with an amine gives a compound represented by the intermediate K. An example of the present disclosure is by reverting the intermediate K to the related naphthylamine derivative followed by the intermediate C or the intermediate D.

Example 54: (R)-N-(4-(4-(3-(3-Tert-butyl-1-p-phenyl)-1H-«bazin-5-yl)ureido)naphthalene-1- Benzyloxy)pyridin-2-yl)-3-(dimethylamino)tetrahydropyrrole-1-carboxamide:

175 S 201111360

Me Example 54 has 4-(4-decylnaphthyloxy) or pyridin-2-amine (2〇〇 mg, 0.71 mmol) and Et3N (〇2〇 ml, i 42亳莫) Phenyl carbonate vinegar (98 μL, 〇78 mmol) was added to dry THF/salt and the reaction mixture was maintained at room temperature for an hour. Add a whole portion of (8)-N,N' dimethyltetrahydropyrrol-3-amine (270 μL, 2.13 mmol) to the mixture and after 15 hours at room temperature a second portion (r) _n, N-dimercaptotetrahydropyrrole_3_amine (1 〇〇 microliter, ο ν 亳 Mo) was added and the mixture was maintained at room temperature for an additional hour. The resulting mixture was partitioned between EtOAc (3 mL) and EtOAc (EtOAc). The combined organic extracts were dried (MgSOS 4) and evaporated in vacuo. The residue was eluted by flash column chromatography (Si 〇 2, 40 g, containing [5% MeOH in DCM] in DCM, 0-100%, gradient elution and then containing 1% [ 2% NH3 (7M in MeOH) in MeOH (EtOAc) elute elute elute elute elute 3·(didecylamino)-N-(4-(4- 176 201111360 succinylnaphthalen-1-yloxy) _2.. yl) tetrahydro guanazone amine (25 〇 mg '81%) 'Intermediate K1; Rt U4 min (method 2); m/z 422 (M+H)+ (ES+). A solution containing intermediate K1 (250 mg, 〇 593 mmol) in MeOH (40 mL) containing AcOH (4 drops) was hydrogenated by EtOAc (1 mL). 25 〇 c, 7 〇 10% Pt / C Cat-Cart 'all hydrogen mode) and then evaporated in vacuum. The crude product was partitioned between EtOAc EtOAc (EtOAc m. Crystalline solid (8)-N-(4-(4-aminonaphthalen-1-yloxy). Bit: base)-3-(dimethylamino)tetrahydroindole small carboxamide (200 mg) , 78%, 9〇% purity); Rt 1.13 minutes (method 2); m/z 392 (M+H)+ (ES+), which was used directly in the next step. In a solution containing CDI (1 mg, 0.370 mmol) in anhydrous DCM (m. (85 mg, 0.370 mmol) and the resulting solution was maintained at room temperature for 2.5 hours. The solution (0.70 ml) was orally added to contain (r)_n_(4-(4-aminocha-1-yloxy) _2_2·yl)-3_(-decylamino)tetrahydrogen The ratio of 11 to 1 per 1 of abatamine (100 mg, 0.255 house moles) in DCM (1.0 ml) was maintained and the mixture was maintained at temperature for 18 hours. The reaction was quenched by the addition of MeOH (3.0 mL) and evaporated. The residue was separated by flash column chromatography (Si〇2, 4 g' containing [5% NH3 (7M on 177 201111360)

</RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; m/z 647 (M+H)+ (ES+); lH NMR (400MHz, DMSO-d6) δ: 1.28 (9H, s), 1.61 (1H, m), 1.98 (1H, m), 2.12 (6H, s), 2.39 (3H, s), 2.58 (1H, m), 3.03 (1H, m), 3.25 (1H, m), 3.49 (lH, m), 3.58 (1H, m), 6.41 (1H, s ), 6.60 (1H, dd), 7.30 (1H 'd), 7.37 (2H, d), 7.44-7.47 (3H, overlap with m), 7·56 (1H 'm), 7.64 (1H, m), 7.83 (1H,d), 7.95 (1H 'd),8·08 (1H,d),8.10 (1H,d),8.70 (1H, s), 8.79 (1H,s), 9.12 (1H,s) . Example 55: N-(4-(4-(3-(3-tert-butyl·ι_p-tolylpyrazole-5)yl)-naphthalen-1-yloxy)»»比味_2 _ base) tetrahydropyrrolamide oxime 02Ν

1. CIC02Ph

Cnh

Intermediate K2

Example 55 Adding phenylcarbonic acid to a solution containing M4-decylnaphthalene+yloxy)oxime-2-amine (just 0.356 millimolar) and Et3N_microliter, 〇7ιιmol THF Stir (10) microliters, 〇) and maintain the mixture at room temperature for 2 hours. The mixture of J 178 201111360 was added between aqueous NH4C1 (10 ml) and DCM (10 ml;) after the addition of a microliter, 1.068 mM. The aqueous layer was separated and extracted with DCM (3.times.10 mL) and the combined organic extracts were dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash column chromatography (40 mL, EtOAc (EtOAc) elute 4·nitronaphthalen-1-yloxy)acridin-2-yl)tetrahydropyrroles small carboxamide (110 mg, 79%), intermediate Κ2; Rt 1.84 min (method 2); m/z 379 (M+H)+ (ES+). A solution containing intermediate K2 (110 mg, 0.29 mmol) in MeOH (20 mL) EtOAc (EtOAc) , 250 C, 70 mm ι / ο Pt / C Cat-Cart, full hydrogen mode) and then evaporated in vacuo. The crude product was partitioned between EtOAc EtOAc (EtOAc m. -Aminonaphthalen-1-yloxy) π ratio _2-yl) tetrahydropyridin-1-yenamide (680 mg, 66%); Rt 1.43 min (method 2); m/z 349 ( M+H)+ (ES+), use it directly in the next step. In a solution containing CDI (100 mg, 0.197 mmol) in anhydrous DCM (1 mL), 3_t-butyl-p-tolyl-1H-pyrazol-5-amine was added portionwise over 20 min. 85 mg, 〇370 mmol) and the resulting solution was maintained at room temperature for 16 hours. One part of this solution (〇6 ml) was added to N-(4-(4-aminonaphthalen-1-yloxy)pyridine-2-yl)tetrachloropyrrole-1-carboxamide (680 g, 0.255亳莫耳) in dCM (1 ml)

The solution of S 179 201111360 was maintained at room temperature for 18 hours. The reaction was quenched by MeOH (2OmL) and the mixture was evaporated in vacuo. The residue was purified by flash column chromatography (Si 〇 2, 4 g, containing [5% MeOH in DC1V [in] in DCM, 0-100%, gradient elution) Compound of the title compound as a brown solid (29 g, 24%), Example 55; Rt 5.00 min (Basic Method 1); m/z 604 (M+H)+ (ES+); lH NMR (400 MHz, DMSO-d6) δ : 1.28 (9H, s), 1.78 (4H, m), 2.39 (3H, s), 3.30 (4H, m ' partially obscured by HOD peak), 6.40 (1H, s) ' 6.60 (1H, dd ) ' 7.30 (1H,d) ' 7.37 (2H,d), 7.45-7.47 (3H, overlap with m), 7.56 (lH,m), 7.64 (lH,m),7·84 (1H, d) ' 7.95 (1H 'd), 8.07 (1H, d), 8.09 (1H, d), 8.63 (1H, s), 8.77 (1H, s), 9.10 (1H, s). Still other examples of the present disclosure are prepared by converting intermediate A to a slow acid represented by intermediate L, followed by reaction of intermediate 1 with an amine under peptide coupling conditions.

180 201111360 Intermediate Ll : 2-(3-(4-(4-(3-(3-tert-butyl-p-p-tolyl-1Η)pyrazol-5-yl)))]naphthalene-1_yloxy Pyridyl-2-yl)ureido)acetic acid

Li〇H/H2〇

Example 37

V χχοΛ:. Co2h

Addition of lithium hydroxide (9 mg, 0.38 mmol) to a solution containing Example 37 (160 mg, 0.252 mmol) in THF (4.0 mL) and water (1.0 mL) At room temperature for 2 hours. Water (5.0 mL) was added and the THF was evaporated in vacuo to remove. The resulting aqueous solution was acidified to pH 3 with hydrogen acid HCl (1 M), and the precipitate thus formed was isolated by filtration to give the compound as a white solid (139 mg, 90%). : Rt 3.72 min (basic method 1); m/z 608 (M+H)+ (ES+); lH NMR (400 MHz, DMSO-d6) δ ppm 1.29 (9H, s), 2.39 (3H 's) ' 3.82 (6H, s), 6.40 (1H, s), 6.79 (2H, br s), 7.35-7.38 (3H, m), 7.47 (2H, d), 7.59 (1H, t), 7.66 (1H, t ), 7.81 (1H, d), 7.99 (2H, d), 8.14 (1H, d), 8.19 (1H, d) ' 8.99 (1H, s), 9.32 (1H, s). Example 56: 2-(3·(4_(4·(3_(3_T-butyl-1-p-tolyl-1H-pyridin-5-yl)ureido)naphthalene+yloxy)pyridine_2 _ base) ureido)-N-methylacetamide

181 S 201111360

Intermediate L1

MeNH^HCI

Example 56 To a solution containing intermediate Ll (3 mg, 0.049 mmol) in DMF (1 5 Φ liter) was added DIPEA (86 μL, 0.49 mmol), EDC (14.2 g, 0.074 mmol) Ear), H0Bt (1 〇〇 1 mg, 〇〇74 mM) and methylamine oxime (33.3 mg '0.494 mmol) and the reaction mixture was maintained at room temperature for 64 hours. The resulting mixture was diluted with methanol (1.0 mL) and acetic acid (4 mL) and purified by SCX capture and elution. The crude product thus obtained was purified by flash column chromatography (Si 〇 2 ' 4 g Shi Xi Shi, MeOH in DCM - 0 - 5 %, gradient elution) to give an off-white solid. The subject compound (9.3 mg, 29%), Example 56: Rt 4.97 min (Basic Method 1); m/z 621 (M+H) + (ES+); lHNMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H , s), 2·40 (3H, s), 2.57 (3H, d), 3.70 (3H, d), 6.41 (1H, s), 6.58-6.60 (1H, m), 6.92 (1H, br s) , 7.32 (1H, d), 7.38 (2H, m), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H, t), 7.81-7.84 (2H, m), 7.96 (1H, d ), 8.07-8.10 (2H, m), 8.20 (1H, br s), 8.79 (1H, s), 9.14 (1H, s), 9.26 (1H, br s). Example 57: 2-(3-(4-(4-(3-(3-Tert-butyl-1-p-tolyl-mn-butyr-5-yl)ureido)naphthalenyloxy) oxapyridine -2-yl)ureido)_N-(2_morpholinoethyl)acetamide 182 201111360

DIPEA (43.0 μl, 0,247 mmol) EDC (23.7 mg, 0123 mmol), H〇, was added to a solution of intermediate Ll (50 mg, 〇 082 mmol) in DMF (1.5 mL). Bt (16 7 mg '0,123 halo) and 2-foethylamine (32 4 μl, 0 247 mmol) and a catalytic amount of dmaP (1 于) at room temperature after 64 hours Mg). After another 24 hours, the reaction mixture was diluted with methanol (1 mL) and then acidified with acetic acid and purified by SCX capture and elution. The crude product thus obtained was purified by flash column chromatography (Si2, MeOH in DCM, EtOAc, gradient elution) Solid title compound (16 mg, 26 ° / 〇), Example 57; Rt 5.03 min (basal method 1); m/z 721 (M+H) + (ES+); lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 2.34 (4H br s), 2.40 (3H, s), 3.18 (2H, br s), 3.54 (4H, br s), 3.73 (2H, br s), 6.41 (1H ' s), 6.58 (1H, dd) ' 6.91 (1H, br s), 7·31 (1H, d), 7.37 (2H, d), 7.46 (2H, d), 7·57 (1H, t) , 7.65 (1H, t), 7.80-7.86 (2H, m), 7.96 (1H, d), 8.07-8.11 (2H, m), 8.27 (1H, br s), 8.82 (1H, s), 9.16 (1H, s), 9.26 (1H, br s). 183 s 201111360 Example 58 · 2-(3-(4-(4-(3-(3-tert-butyl-p-p-phenyl)-m-nfc)-) Morpholine

〇〇H

Intermediate L1 — __ DIPEA 〇Bt, DIPEA (52 μL, 0.290 mmol), EDC (28.4 mg) in a solution containing intermediate LI (60 mg, 0.099 mmol) KDMF (15 liter) '〇.148 millimolars, H0Bt (2〇() mg, 〇148 mM) and 福福咁 (26 μl '0.296 mmol) and the reaction mixture was maintained at room temperature 16 hours. The resulting mixture was diluted with methanol (1 〇 pen: liter) and then acidified with acetic acid and subjected to sCx capture and release. The crude product thus obtained was purified by flash column chromatography (Si2, MeOH in EtOAc EtOAc EtOAc The title compound was obtained as a white solid (25 mg, 36%), </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; δ ppm 1·28 (9H, s), 2.40 (3H, s), 3.36-3.38 (2H, m), 3.41-3.43 (2H, m) ' 3.53-3.57 (4H, m), 3.99 (2H ' d) '6·41 (1H ' s) ' 6.58 (1H, dd), 6.94 (1H, br s), 7.32 (1H, d), 7.37 (2H, d), 7.46 (2H, d), 7.57 ( 1H, t), 7.64 (1H, t), 7.82 (1H, d), 7.96 (1H, d), 8.06-8-08 184 201111360 br s), 9.13 (1H, (2H ' m), 8.18 (1H 'brs), 8 79 (m, s), 9.32 (1H, s). Tributyl-1_p-tolyl-1H-pyridine Example 59 : 2-(3-(4-(4-(3-( 3. tert-butyl fluoren-5-yl) glycosyl) naphthalene 1 yloxy) benzyl 2) gland) _n (2 octyl-4-yl) hexyl)

DIPBA (52 μL, G.296 mmol), EDC (28.4 mg '0,148 mmol) was added to a solution containing intermediate L1 (6 g mg 'mmol) in DMF (15 mL). , H〇Bt (2 mg, 〇148 mM) and 2-(pyridin-4-yl)ethylamine (36 2 mg, 〇2% mmol) and the reaction mixture was maintained at room temperature 16 hours. The resulting mixture was acidified with acetic acid (0.2 mL) and subjected to scx capture and elution. The crude product thus obtained was purified twice by flash column chromatography (Si 〇 2 ' 12 g, containing [7M NH3 in MeOH] in DCM - 0-5%, gradient elution then ;Si〇2, containing {5%[7M NH3 in

MeOH <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Minutes (method 2); m/z 712 (M+H)+(ES+); lH NMR (400 MHz, DMSO-d6) δ ppm 1·28 (9H 's), 2.39 (3H, s), 2.71 ( 2H, t), 3.28-3.32 (2H, m), 3.69 (2H, d), 6.41 (1H, s), 6.57 (1H, dd), 6.92 (1H, br s), 7.21 185 s 201111360 (2H ^ d), 7.31 7.37 (2H&gt;d)&gt; 7.46 (2H&gt;d), 7.57 (1H 't), 7·64 (1H,t), 7.82 (1H,d),7 95 (ih, d) ' 8.01(1H,t),8.07-8.09 (2H,m),8.22 〇H,b 8.43 (2H,d) ' 8.78 (1H ' s), 9.12 (1H,S), 9.24(1H, s) o Example 6〇: smear small base) propyl)_2-(3_(4_(4 (3 (3_t-butyl-1-yl-p-phenyl-1H-indole, 5, yl-amino) 〇 咬 -2- 基 基 基 基 )

DIPEA (43 μL, 0.247 mmol), EDC (31.5 mg '0.167 mmol), H, was added to a solution of intermediate L (5 mg, 0.082 mmol) in DMF (15 mL). 〇Bt (22 2 mg, 〇165 mmol) and 3-(1Η-imidazol-1-yl)propan-amine (3〇9 mg, 〇247 mmol) and maintain the reaction mixture in the chamber Wenda is 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (2························ And evaporate in vacuo. The residue was purified by flash column chromatography (Si 2 , 4 g, containing {5% [7MNH3 in MeOH] in ethyl acetate] in hexane, 5 〇_1〇〇0/〇, gradient elution) was purified to give the title compound as a white solid (13 mg, 22 〇 / 〇), Example 60: Rt 1.90 min (method 2); m/z 715 (M +H)+ (ES+); 186 201111360 lH NMR (400 MHz, DMSO-d6) δ ppm 1.28 (9H, s), 1.75-1.85 (2H, m), 2·40 (3H 's), 2.99-3.04 (2H,m), 3.73 (2H,d),3.94 (2H 't),6.41 (1H, s), 6.57 (1H, dd), 6.87 (1H ' br s), 6.93 (1H, br s), 7·15 (1H, s), 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, d), 7.55-7.59 (2H, m), 7.65 (1H, t) ' 7.82 (1H, d), 7.94-7.98 (2H, m), 8.07-8.09 (2H 'm), 8.25 (1H, br s), 8.79 (1H, s), 9.13 (1H, s), 9.24 (1H, s). Example 61: 1-(2-(3-(4-(4- (3-(3-Tertibutyl-i-p-tolyl-1 £[-pyrazol-5-yl)ureido)naphthalenyl-yloxy)pyridine-2-yl)ureido)ethinyl) -4-methylhexahydropurine

DIPEA (43 μL, 0.247 mmol), coffee (31.5 mg, 167.167 mmol), was added to a solution of intermediate L1 (50 mg, 0.082 mmol) in DMF (1.5 mL). H〇Bt (22 2 mg, 〇·(6) imomol) and 1-mercaptohexahydro-tI ratio tillage (24.72 mg, 〇247 mmol) and the reaction mixture was transferred to a temperature of 1 Μ. The resulting mixture was diluted with water (5 liters) and extracted with ethyl acetate (2 X 1 mL) and combined organic extracts (4) water (2 χ 1 () mL dry (MgS 〇 4) ' and in vacuo蒗狢曰 成 成 丄 β ββ +... Dry (MgS〇4),

S 187 201111360 '0-5%, gradient elution) was purified and SCX captured and released. The product thus obtained was dissolved in DCM (0.3 mL) and isohexane (2.0 liter) was added. The white precipitate was isolated by filtration and flash-column chromatography (Si 〇 2, 12 g, containing [7 Μ ΝΗ3 in MeOH] in DCM, 0-5% gradient elution) Purified to give the title compound as a white solid (9 mg &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& D6) δ ppm 1.28 (9H, s), 2.17_2·50 (10H, m), 3.24-3.51 (4H, m), 3.97 (2H, d), 6.40 (1H, s), 6·58 (1H ' Dd), 6.94 (1H, br s), 7.31 (1H, d), 7.37 (2H, d) ' 7.46 (2H 'd), 7.57 (1H, t), 7.64 (1H, t), 7.82 (1H, d), 7.95 (1H, d), 8.06-8.10 (2H, m), 8.16 (1Η, br s), 8.80 (1H, s), 9.13 (1H, s), 9.30 (1H, s). Example 62: N-(3-(lH-imidazol-1-yl)propyl)-2-(3-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H) -&quot;Bizozol-5-yl)ureido)naphthyloxy)0-biti-2-yl)glycine)acetamide

Add DIPEA (43 μl, 0.247 mmol) to EDC (31.5 φg '0.167 mmol)' HOBt (1 ml) in a solution containing intermediate L1 (50 mg, 0.082 mmol) in DMF (1.5 mL) 22.2 mg, 0.165 mmol, and 2-methoxyethylamine (21.5 μl, 0.247 mmol) and maintained at room temperature for 6 hours. The resulting mix 188 201111360

Clock (basic method 1); m/z 665 (M+H)+(ES+) ; 1H NMR (4〇〇MHz, DMSO-d6) δ ppm 1.28 (9H, s), 2·4〇 (3H, s ), 3.19-3.23 (5H, m), 3.30 (2H, t), 3.73 (2H, d), 6.41 (1H 's) ' 6.57 (1H, dd), 6.93 (1H, br s), 7.31 (iH , d), 7 37 (2H, d), 7.46 (2H, d), 7·57 (1H, t), 7.64 (1H, t), 7·82 (1H, d), 7.94-7.99 (2H, m) ' 8.07-8,09 (2H,m), 8.19 (1H ' br s) ' 8.77 (1H,s) ' 9.12 (1H, s), 9.23 (1H, s). Other examples of the present disclosure are produced by the intermediates (when the tea-based amine derivative) and the intermediate N (in the case of the amino-based organisms) by reaction with the intermediate C or the intermediate D.

Intermediate Ml : N-(6-(4-Aminonaphthalen-1-yloxy)pyrimidine_4_yl)_2-methoxyacetamide

S 189 201111360

6-(4-Complementary Tea-1-yloxy) Bite 4-amine containing 6-aminopyrimidine-4(3H)-one (866 g, 7.79 mmol) in DMSO (10.0 DKB (i 29 house liter, 8.57 house Moule) was added to the solution at room temperature and after 1 minute it will contain 1_fluoro_4_ stone succinyl naphthalene (1.57 g, 8.18 mmol) to DMS0 (3 〇 The solution of cc) was added during 2 minutes and 4 minutes. The resulting mixture was maintained at room temperature for 2 h and diluted with MeOH (20 mL) and TFA (2. The ahai/troche solution was subjected to SCX capture and release and the crude product thus obtained was washed by flash column chromatography (Si 〇 2, 80 g, EtOAc in isohexane, 50-100%, gradient elution) The title compound was obtained as a yellow solid (370 mg, 16.48%); Rt 3.82 min (Basic Method 1); m/z 283 (M+H)+ (ES+). 2-methoxy-N-(6-(4-nitronaphthalen-1-yloxy)- oxaridin-4-yl)acetamide containing 6-(4-nitronaphthalen-1-yloxy) ) Cyclopyridin-4-amine (350 mg, 1.24 mmol) in a suspension of Dcm (1 〇.〇 ml) and DIPEA (433 μl, 2·48 mmol) at 0 °C曱 醯 醯 醯 Π (Π 0 μl ' 1.860 millimoles). The mixture was warmed to rt. EtOAc (3M, EtOAc) The residue was partitioned between DCM (30 mL) EtOAc (EtOAc) The residue was purified by flash column chromatography (40 g, MeOH in EtOAc (EtOAc) elute Mg, 86%); Rt 4.60 min (basic method 1); m/z 355 (M+H)+ (ES+). Intermediate Ml: N-(6-(4.Aminonaphthalenyloxy)octyl)-methoxyacetamide will contain 2-decyloxy-N-(6-(4-nitrogen) a mixture of carbaryl-1 - yloxy)pyrimidine _4_ yl) ethanoamine (4 〇 0 mg, 1.13 mmol) in MeOH and DCM and AcOH (2. 2:1 vol/v, 15 mL) The solution was obtained by hydrogenation by a Taylors H-cube (1 liter. min -1, room temperature, 55 mm CatCart, l〇〇/oPt/c 'per hydrogen mode) and then evaporated in vacuo. The compound was obtained as a brown oil (4 〇〇 &lt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Intermediate N1: N-(6-(4-Aminophenoxy)glycine-4-yl)-2-methoxyacetamide

S 191 201111360

Intermediate N1 6-(4-mercaptophenoxy)-trigested tert-butyl 4-methylaminocarbamate will contain 4-gas-6-(4-nitrophenoxy)pyrimidine (w〇2006072589) ( 1.50 g '5.96 mmol), tert-butyl carbazate (2 1 gram, 17 9 moles) 'sour bismuth (2.91 g, 8_94 mmol), Pd2dba3 (0.218 g, 0.238 mmol) Ears and Schaffer (〇276 g, 〇477 mAh) degassed mixture in DMF was heated at reflux for up to hrs and then maintained at room temperature for 16 hours. The resulting mixture was distributed in water (1 〇) 〇ml) and EtOAc (100 ml) and the organic layer was separated and washed with water (5 mL) and brine (50 liters) and then dried (MgS 〇 4) and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) elute Purity, 52%); Rt 4.90 minutes (basic method 丨); m/z 331 (MH) _ (order). 4-Amino-6-(4-propenylphenoxy) pulverized to a third butyl vinegar containing 6-(4-nitrophenoxy)pyrimidin-4-ylcarbamic acid (1.22 g '85% purity) To a suspension of DCM (12.0 liters) was added TFA (1.4 mL, 18, 4 mM) and the mixture was stirred at room temperature for 1 hour. The whole portion of TFA (〇7〇亳192 201111360) will maintain the mixture in the room to evaporate. The residual makeup #T and ..., 汲方, 兴htv cloth in Et0Ac (5 〇 ml) and saturated water Γ 25 弁Between 1 and 1 (50 liters) and separate the organic zan and use the salt U and then dry (Mgs 〇 4). The volatiles were decanted in vacuo and passed to the standard compound (0.66 g) as a yellow solid. , 89%), Rt 丨.38 min (method 2); m/z 233 (MH) + (ES+). 2-methoxy-indole-(6·(4-jingyl)oxy) _4 Ethylamine is contained in 4-amino-6-(4-nitrophenoxy) (56 mg, μ mmol) and DIPEA (630 μl, 3,62 mmol) in dcm ( Ϊ́5 ml) in 〇. (: 2 曱 曱 乙 ( 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 330 The reaction was quenched by the addition of 1% NH3MMe(R) in a solution (1 liter) and then evaporated in vacuo. The residue was partitioned between DCM (50 mL) and water (25 mL) and The organic layers were separated and washed with brine (25 mL) and then dried (MgS 〇 4). The title compound was obtained as a beige solid (yield: 730 mg &lt;&lt;&gt;&gt; 97%) &lt;RTIgt;&lt;/RTI&gt; (6_(4·Aminophenoxy), _4_yl)_2_decyloxyacetamide will contain 2_methoxy-indole-(6·(4-Shidocylphenoxy) η Ice based)

A solution of the amine (730 mg, 2.53 mmol) in a mixture of MeOH and DCM (1:1 v/v, 80 mL) containing AcOH (5 drops) by hydrogenation by the syllabs H-cube (1 〇ml minutes

S 193 201111360 -ι, room temperature, io%pt/c, full hydrogen mode) and then evaporated in vacuum. The residue was partitioned between DCM (100 mL) and sat. NaHC. The organic layer was separated and washed with brine (25 mL) and then dried (MgSO.sub.4). The volatiles were evaporated in vacuo to give the title compound, Intermediate N1, (560 g, 66%, estimated purity 82%); Rt 0.93 min (method 2); m/z 275 (M+H)+ (ES+ ). This material was used directly in the next step without further purification. Example 63: Ν·(6-(4-(3-(3·t-butylbutyl-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy), bite_4 _ yl)-2-methoxyacetamide

Containing 3-tert-butyl-1-p-tolyl_pressure-吼-salt-5-amine (509 mM

克 ' 2.220 mmoles) was added to a solution of DCM (1 〇.〇 ml) to CDI (360 克, 2.22 house moles) and the reaction mixture was maintained at room temperature for 3 hours to give intermediate d3 Solution [batch η. In a similar manner, an additional amount of activated 3-D-butyl-p-tolyl-1-indole-pyrazole-5-amine (7.57 g, 33.0 mmol) in DCM (5 mL) can also be used. The aminopyrazole was reacted with CDI (5.36 g, 33 mmol) at room temperature for 3 hours to give a second solution containing intermediate D3 [batch 2]. 'An ancient solution containing intermediate Ml (36 g, i 00 mmol) in DCM (6 liters) was added to a solution containing intermediate D3 [batch U as prepared before and the mixture was Maintain at room temperature for up to hrs. A second portion of 194 201111360 adduct (3.0 ml, batch 2) was added and the reaction mixture was maintained at room temperature for 16 hours and evaporated on a vermiculite in vacuo and the residue was purified by flash column chromatography Separation (Si 2 , 12 g, EtOAc in iso-hexane, 0-100%, gradient elution) was purified. The crude material thus obtained was taken up in DCM (3 mL), and then Et. The precipitate was extracted into boiling EtOAc (3.0 mL), cooled to &lt;RTI ID=0.0&gt;&gt;&gt; The precipitate of Batch P1 was dissolved in MeCN (2.0 mL), water (2.0 mL) was added and the mixture was warmed to boiling and then cooled to 〇 ° C and finally maintained at room temperature for 16 hours. The formed precipitate was collected by filtration and combined with batch P2 to give the title compound (120 mg, &lt;RTI ID=0.0&gt; 580 (M+H)+ (ES+); W NMR (400MHz, DMSO-dQ δ: 1.28 (9H, s), 2.40 (3H, s), 3.33 (3H, s), 4.10 (2H, s), 6.41 (1H, s), 7.34-7.39 (3H, overlap with m) ' 7.46 (2H, m), 7.55 (1H, m), 7.63 (1H, m) ' 7.66 (1H, d), 7·77 (1H , d), 7_92 (1H, d), 8.06 (1H, d), 8.45 (lH, d), 8.78 (lH, s), 9.12 (lH, s) and 10.71 (1H, s) o Example 64: N -(6-(4-(3-(3-tert-butyl-l-p-tolyl-111-«bazin-5-yl)glycosyl)phenoxy)pyrimidin-4-yl)_2_曱Oxyacetamide

195 S 201111360

Intermediate N1

Intermediate D3 (Bu

Example 64 has 3 CDI (296 mg, 1.82 mmol) in DCM (5 〇 = = =, 3. butyl butyl in the float) • p-tolyl _m• 5 5 _ amine; Add 1 part of Maoke 1,82 $ moles and add the reaction mixture to room temperature for 4 hours. Add the solution containing intermediate D3 (2·7 mAh) to the intermediate containing the previous preparation. N1 (100 mg, 82 〇/〇, : 曰: 0.30 mmol) in DCM (1·5 mL) and maintained at room temperature for 16 hr. MeOH (2.0 liters) was quenched, and then the mixture was evaporated in EtOAc EtOAc EtOAc (EtOAc) Purification by 25-75%, gradient elution to give the title compound as a pale brown solid (5 </ RTI> </ RTI> </ RTI> 25 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Rt 2.43 min (method 2); m/z 530 (M+H ) + (Es+) ; 1h NMR (400MHz ' DMSO-d6) δ : 1.27 (9H, s), 2.38 (3H, s) , 3.33 (3H, s), 4.08 (2H, s), 6.30 (m, s ) ' 7.11 (2H ' d), 7.34 (2H, d), 7·39 (2H, d), 7.46 (2H, d) ' 7.50 (1H, s), 8.36 (1H, br s), 8.50 (1H, s), 9.11 (1H's), 10.64 (1H, brs). Other examples of the present disclosure are produced by the N-deuteration reaction of a compound represented by the intermediate p. 196 201111360

Intermediate PI: 1-(4-(2-aminopyrimidinyloxy)indenyl)_3_(3·t-butyl-1-p-tolyl-1Η-pyrazole-5-yl) 11

Me Intermediate P1 4-butyl 2-(2-chloroindol-4-yloxy)naphthalen-1-ylaminocarbamate in tert-butyl 4-cyclonaphthalen-1-ylaminocarbamate (133) Gram,

51.3耄莫耳) and DBU (12.6 ml, 51.3 mmol) in a degassed solution of MeCN (80 liters), containing 2,4 dichloropyrimidine (7.65 g, 51.3 mmol) under nitrogen Acetonitrile (19 mL) and the reaction mixture was heated to reflux for 4 h. The solvent was evaporated in vacuo and EtOAc (EtOAc)EtOAc. The residue was purified by flash column chromatography (Si 〇 2, 33 gram, eluted with Et~Ac in iso-hexane, '0-50%' gradient) to give a pale powder &amp; 197 201111360 Red solid standard compound (6.80 g, 34%); Rt 2.50 min (method 2); m/z 372/374 (M+H)+, (ES)+. T-butyl 4-(4-(t-butoxycarbonylamino)naphthyloxy)pyrimidine-2-ylaminocarbamate containing tert-butyl carbamic acid ester (1.89 g, 16.1 mmol) , 4-(2-Apyrimidin-4-yloxy)naphthalenecarbamic acid tert-butyl ester (2 gram ' 5.38 mmol) ' Cs2C 〇 3 (4.38 g, 13.45 mmol) and To a degassed suspension of THF (50 ml) was added Pd2dba3 (197 mg, 0.215 mmol) and the reaction mixture was heated at 75 °C for 16 h. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The aqueous layer was separated and extracted with EtOAc (40 mL)EtOAc. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) elute 〇); Rt 2.53 minutes (method 2); m/z 453 (M+H)+, (ES)+. 4-(4-Aminonaphthyloxy)pyrimidine-2-amine containing tert-butyl 4-(4-(t-butoxycarbonylamino)naphthyloxy)pyrimidin-2-ylaminocarbamate ( To a solution of EtOAc (15 mL) was added &lt;RTI ID=0.0&gt;&gt; The mixture was evaporated in vacuo and EtOAc (EtOAc)EtOAc. 198 201111360 Evaporated in vacuo to give the title compound as a beige solid (735 gram '96%); Rt ο·% min (method 2); m/z 253 (M+H)+, (ES)+ 〇 middle PI: 1-(4-(2-aminopyrimidin-4-yloxy)naphthalene·1·yl)_3_(3_t-butyl-p-p-tolyl-1Η-pyrazol-5-yl)urea Add 1 g portion of 3_t-butyl-1-p-tolyl-1H-indazole-5- in a suspension of CDI (17.24 g, 106 mmol) in DCM (150 mL) over 40 min. Amine (24.38 g, 106 mmol) and the reaction was stirred at room temperature for 2 h. This solution (5.0 mL) was added dropwise to a mixture containing 4-(4-aminonaphthalen-1-yloxy)pyrimidin-2-amine (720 mg, 2.85 mmol) in DCm (15 mL) The suspension was maintained in the suspension at room temperature for 2 hours. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) ), intermediate P1, ; 応 2.12 min (method 2); m/z 508 (M+H)+, (ES)+. Intermediate PI: 1-(4-(2-Aminopyrimidin-4-yloxy)naphthalene)-3-(3_t-butyl-1-p-tolyl-1H-indazol-5-yl) Urea [Pathway 2] 199 S. 201111360

OMe

Intermediate P1 4-(4-Aminonaphthalen-1-yloxy), 唆_2_amine [Pathway 2] Containing 4-(2-chloropyrimidin-4-yloxy)naphthalene-based decanoic acid Adding (4_methoxyphenyl) to the solution of the third vinegar (1.00 g, 2.69 mmol) and triethylamine (〇374 ml, 2 69 mmol) in DMSO (10 ml) (350 microliters, 2.69 house moles) and the reaction mixture was heated in a sealed tube at 95 °C for 16 hours. The resulting mixture was partitioned between water and EtOAc. EtOAc was separated and washed with brine and then dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (Si〇2' containing acetic acid in the same room, 〇_5〇%, gradient elution) to obtain [by LCMS evaluation] a 1: 1 mixture of compound: 4-(2-(4-decyloxybenzylamino) succinyl-4-yloxy)naphthalen-1-ylaminocarbamic acid tert-butyl ester with methoxy Base) Coffee _4_amine together. This material was used directly in the next step without further purification. It will contain the third pure vinegar (〇77g, ~5 purity, 0.8mmol) in TFA (as a pure 4th serotonyl amido-4-yloxy)naphthalene amide. 1 〇 up to 8 hours and then maintained in the room: far-flowing in the return force: you μ acre by -a for hours. The reaction thirst is in the real work and the residue is extracted to Et0Ac and used 200 201111360

The aqueous solution of NaHC 3 was washed with brine and then dried (MgS 4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si2, ethyl acetate in isohexane, 5 〇-1 〇〇〇 /0, gradient elution) to give a brown solid. Compound (ηι mg, 54%); m/z 253 (M+H)+, (ES)+. Example 65· Ν-(4-(4-(3-(3·T-butyl-1-p-tolylpyrimidin-5-yl))yl)-naphthalen-1-yloxy)-purchase-2- 2-methoxyacetamide

Add DIPEA (114 μl, 0.640 mmol) and 2-methoxy at 0 °C in a solution containing intermediate Ρ1 (65 gram 〇 128 亳 Mo) in DCM (20 mL) Ethyl chloride (35 μL, 〇·38 mmol) and the reaction mixture was warmed to room temperature for 16 h. The reaction was quenched by the addition of 1% EtOAc (2 mL) EtOAc (EtOAc). The residue was partitioned between dcm (5.0 mL) and saturated aqueous NaHCO3 (5 mL) and the organic phase was separated and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc EtOAc EtOAc (EtOAc) The title compound was obtained as a white solid (13 mg, 17%), s. 65; Rt 2.37 min (method 2); m/z 580.1 (M+H)+, (ES)+. iH NMR (400 MHz ' DMSO -d6) δ : 1.28 (9H, s), 2.40 (3H, s), 3.04 (3H ' s), 3.70 (2H ' s) ' 6.41 (1H, s), 6.84 (1H, 201 201111360 d), 7.38 -7.45 (5H, overlap with m), 7.57 (1H, t), 7.64 (1H, t) ' 7.78 (1H,d), 7.96 (1H,d),8.08 (1H,d),8.53 (1H, d ), 8.76 (1H, s), 9.13 (1H, s), 10.30 (1H, s). Other examples of the present disclosure are obtained by reacting intermediate P with an isocyanate and by converting intermediate P to intermediate Q followed by reaction with an amine.

Example 66: 3-(4-(4-(3-(3-Tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyrimidine -2-yl)urea Intermediate P1

Contains intermediate P1 (65 mg, 0.128 mmol). Trichloroethendyl isocyanate (24.1 mg, 0.128 mmol) was added to a solution of the pyridine (2.0 mL) and the reaction mixture was maintained at room temperature for 16 hours 202 201111360. The reaction was quenched by the addition of 1% aq. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc:EtOAc) Compound (24 mg, 32%), Example 66; Rt 2.30 min (Method 2); m/z 551.0 (M+H) + (ES+); lH NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s ), 2.40 (3H, s), 6.41 (1H, s), 6.63 (1H, d), 0.76 (1H, br s), 7.39-7.45 (5H, overlap with m), 7.58 (1H, t), 7.64 (1H,t),7_79 (1H,d) ' 7.82 (1H,br s),7.96 (1H,d),8.08 (1H,d),8.44 (1H,d),8.79 (1H,s),9.11 (1H, s), 9·45 (1H, s). Intermediate Q1: propan-1-ylidene-2-yl 4-(4-(3-(3-tert-butyl-1-p-tolyl-1H_indole than sal-5-yl)ureido)-steaming 1-yloxy)pyridin-2-ylcarbamate

Intermediate Q1 was dissolved in a solution of Intermediate P (1.14 g, 2.246 mmol) and NMM (370 μL, 3.37 mmol) in THF (20 mL). The prop-1-en-2-yl carbonate chlorate (365 μl, 3 37 mmol) was added dropwise and the reaction mixture was stirred at 〇 ° C for 5 hours. The resulting mixture was diluted with EtOAc (20 mL) and washed with sat. NaHC.sub.3 solution (20 liters) and brine (20 mL) and then dried (MgS 〇4)

S 203 201111360 Evaporation in vacuo gave intermediate q (1 g, 81%) as a beige solid; Rt 2.58 min (method 2); m/z 592 (M+H)+, (ES)+. Example 67· 1-Methyl-3-(4-(4-(3-(3-tert-butyl-1-p-tolyl·m-pyrazol-5-yl)ureido)naphthyloxy)pyrimidine _2 base) urea:

Add guanamine (21V) to a suspension of intermediate Q1 (70 mg, 〇118 mmol) and 4-methylmorpholine (1.3 μl, 12 mM) in THF (5.0 mL). In THF, 89 μl, 0.177 mmol, and the 5 hr reaction mixture was heated in a closed tube at 55 ° C for 16 hours. The reaction mixture was cooled to room temperature and distributed between Et EtOAc (1 mL) and water (10 mL). The organic layer was washed with brine (10 mL) and dried (MgSO. The residue was purified by flash column chromatography (Si2, eluted with MeOH in DCM, 0-5% gradient elution) and then recrystallized from methanol to give RV1581 as a white solid. </ RTI> <RTIgt; 9H, s), 2·23 (3H, d), 2.39 (3H ' s), 6.41 (1H, s), 6.77 (1H, d), 7.37 (2H, d) ' 7.42-7.47 (3H, and m Overlap), 7.59 (1H, t), 7.66 (1H, t) ' 7.78 (1H, d), 7.84 (1H, br s), 7.97 (1H, d), 8.09 204 201111360 (1H, d), 8·47 (1H, d), 8.74 (1H, s), 9.16 (1H, s), 9.64 (1H, s). Example 68.1, 1-monomethyl_3_(4-(4_(3_(3_t-butyl-p-p-tolyl-1Η-°-salt-5-yl)))-naphthalene-yloxy) bite 2 base) urea

Intermediate Q1

NMM

MezNH

Example 68 Addition of diamine to a suspension of intermediate Ql (70 mg, 118 mmol) and 4_mercaptophyrin (1.3 μl of '12 mmol) in THF (1 mL) 2M in THF, 89 [mu]L, 177 mmoles) and the reaction mixture was heated in a closed tube at 55[deg.] C. The reaction mixture was cooled to room temperature and distributed between Et EtOAc (1 mL) and water (1 mL). The organic layer was washed with brine (1 mL) and dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si 〇 2 ' MeOH in DCM, EtOAc EtOAc EtOAc EtOAc , 20-70%, gradient elution) and purified by preparative HPLC (reverse phase EtOAc, water/MeCN gradient) to give compound as a white solid (16 mg, 22%). Minutes (basic method 1); m/z 579 (M+H)+, (ES+); lH NMR (400MHz, DMSO-d6) δ ·· 1.28 (9H, s), 2.39 (3H, s), 2.71 ( 6H, s), 6.39 (1H, s), 6.53 (1H, d), 7.36-7.39 (3H, overlap with m), 7.46 (2H, d), 7.57 (1H, t), 7.63 (1H, t) , 7.80 (1H,d),7.89 (1H, 205 £ 201111360 d) ' 8·06 (1H,d),8.37 (1H,d),8.83 (1H,s),9·14 (1H 's), 9.18 (1H, s). Example 69: 1-cyclopropyl_3_(4·(4_(3_(3 tert-butyl-p-tolyl-1Η-» than 嗤-5·yl))-naphthalenyloxy))) Urea

Add cyclopropylamine (12.3 μl' to a suspension of intermediate Q1 (70 mg, 118 mmol) and 4-methylmorphin (1.3 μL, 12 mmol) in THF (10 mL) 177 mmoles and the reaction mixture was heated at 50 °C for 96 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (EtOAc) The organic layer was separated and washed with brine (10 mL), dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) elute , Example 69; Rt 2.53 min (method 2); m/z 591 (M+H) + '(ES+); 1H NMR (400 MHz 'DMSO-d6) δ: -0.25 (2H 'm) ' 0.26 (2H, m), 1.29 (9H, s), 2.22 (1H ' m), 2.39 (3H, s), 6.42 (1H, s), 6.78 (1H, d) ' 7.38-7.46 (5H, overlap with m), 7 58 (ih, t) , 7.66 (1H,t) ' 7.76 (1H,d) ' 8.00 (1H,br s),8 03 (1H, d), 8.12 (1H,d),8.47 (1H,d) , 8.78 (1H, s), 9.17 (1H, s), 9.66 (1H, s). 206 201111360 Example 70: (4-(4-(3-(3-Tert-butyl-1-p-tolyl)!!-»Bizozol-5-yl))-naphthalen-1-yloxy)咬--2-yl) whallin-4-carboxyguanamine

Add Fukufon (15.6 μl) to a suspension of intermediate Q1 (70 mg, 118 mmol) and 4-methylfosfolium (1.3 μL, 12 mmol) in THF (10 mL) , 177 millimoles) and the reaction mixture was heated at 55 °C for 16 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (EtOAc) The organic layer was separated and washed with brine (10 mL) and then dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash column chromatography (Si2, eluting with MeOH in DCM eluting elute Mg, 27%), Example 70; Rt 2.26 min (method 2); m/z 621 (M+H)+, (ES+); iH NMR (400 MHz 'DMSO-d6) δ: 1.28 (9H, s), 2.40 (3H, s), 3.25 (4H ' m) ' 3.46 (4H, m), 6.40 (1H, s), 6.56 (1H, d), 7.38-7.40 (3H, overlap with m), 7 46 (2H , d), 7.57 (1H 't), 7.63 (1H, t) ' 7.81 (ih,d), 7.90 (1H, d) ' 8.06 (1H,d), 8.40 (1H 'd), 8.75 (ih, s), 9.10 (1H, s), 9.38 (1H, s). Still other examples of the present disclosure are obtained by reacting a compound represented by the intermediate R with an intermediate C or an intermediate d. 207 201111360

Intermediate C

OR Intermediate D

Intermediate ^

Intermediate Ri propyl-1 ketone 2-yl 6·(4_decylnaphthalene yloxy) sulphonic -4-amino amide containing 6-(4-nitronaphthalene-fluorenyloxy)pyrimidinamine 89 mg, 〇·315耄莫耳) and NMM (45 μl, 〇.41 〇 mmol) in THF (2.0 liters) in 〇〇c dropwise added propylene-2-carboxylate A solution of the ester (45 μL, 0.410 mmol) in THF (1 mL) and warmed to room temperature for 15 h and then partitioned between EtOAc (20 mL) and water (5 mL) . The aqueous layer was separated and extracted with EtOAc (EtOAc EtOAc (EtOAc) 2); 111/2 367 (]^+11)+(£8+). This material was used directly in the next step (see below) without further purification. 208 201111360 1-(6-(4_Acetylnaphthalene-fluorenyloxy) squirting ice-based) veins containing prop-1--l-yl-2-yl 6-(4-nitronaphthalene + yloxy) Adding a solution containing a NH3 to a solution of a solution of keto-glycolic acid citrate (109 mg '0.298 mmol) and 4 曱 吗 吗 啩 (3.3 μl '0.030 mmol) in anhydrous THF (27 mL) A solution in MeOH (0.6 mL, 1M + EtOAc &lt;EMI&gt; The other parts of the NH3 solution of methanol were added after 1 hour (0.6 mL, 〇6 mmol) and after 5 hours (1.0 mL, 1 mmol), and after another 16 hours, the reaction mixture was vacuumed. Evaporation. The residue was extracted into THF (liters) and NMM (3.3 μL, 0.030 mmol) and Me〇H (0.6 mL, m, 0.6 mmol) were added and the reaction mixture was heated to 55°. C. The other whole A, iNH3 solution (1 M, 1 宅 升 ' 1.0 耄 Mo) was added after 2 hours, and after 3 hours. After 3 hours, an additional portion of NMM (3.3 μL, 0.030 mmol) and methanol in NH3 (1M, 1.0 mL, 1. 〇m) were added and the mixture was maintained at 55 ° C. hour. The reaction mixture was evaporated in vacuo and purified title title title title title m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m The title compound of the solid (6 mg, 61%); Rt 1.87 min (method 2); m/z 326 (M+H)+ (ES+). Intermediate Rl: 1-(6-(4-Aminonaphthalen-1-yloxy) pyridyl)urea will contain 1-(6-(4-nitronaphthalen-1-yloxy)pyrimidine_4 • base urea (6 mg, 0.184 house moles) in a mixture of OH, DCM and THF (1:1:1 volume/vol/vol, 3 mL) containing AcOH (2 drops) 209 201111360 &gt; The trough is hydrogenated by passing the Thales H_cube (1 〇 ml·min_1 'room temperature' 70 mm CatCart, 10% Pt/C, full hydrogen mode). The resulting solution was evaporated in vacuo to give the title compound (jjjjjjjjjjjjjjjjj M+H)+ (Ε§+). The haibeibei was used directly in the next step (below) without further purification. Example 71: 3-(6-(4-(3-(3-Tertibutyl)-1-p-tolyl-1Η-pyridyl) Azole _5_yl) ketone)naphthalen-1-yloxy) mouth bite _4-base) gland

Add in a suspension containing CDI (17.24 g, 106 mmol) in DCM (150 mL) over 40 min! The amount of 3-tert-butyl-1-p-tolyl-1H-pyrazole-5-amine (24.38 g, 106 mmol) was stirred and the mixture was stirred at room temperature for 2 hr. An aliquot of this solution containing intermediate D3 (〇·36 mL) was added to a solution containing intermediate Rl (58 mg, 0.179 mmol) in DCM (500 <RTIgt; Up to 1.5 hours. The reaction was quenched by the addition of MeOH (5 mL) and EtOAc was evaporated in vacuo and the residue was evaporated in vacuo. % MeOH in EtOAc <RTI ID=0.0># </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Wash with water (5.0 mL) and brine (5 mL) then dry (M.sub.4) and evaporated in vacuo. The residue thus obtained was dissolved in EtOAc (EtOAc (EtOAc)EtOAc. , 34%), Example 71; Rt 2.23 min (method 2); m/z 551 (M+H)+ (ES+); 1HNMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 2.39 (3H , s), 6·41 (1H ' s), 6.80 (2H, br peak), 7.22 (1H, s), 7.32 (1H 'd), 7.37 (2H, d), 7.46 (2H, d), 7.56 (1H, m), 7.62 (1H, m), 7.77 (1H, d), 7.90 (1H, d), 8.06 (1H, d) ' 8.31 (1H, s), 8.77 (1H, s), 9.10 ( 1H, s), 9.52 (1H, s). Biological Testing All of the compounds exemplified herein showed Ι〇5〇&lt;5μΜ for ρ38α in the enzyme activity assay. Examples of selected compounds that have a broader mode of action are shown in Tables 1-3 below. 1 case code λ real number

ΤΗΡ-1 DU937 DU937 BEAS2B DU937 (LPS) (LPS) (LPS) (polylC) (cell motility) TNFa TNFa IL-8 ICAM1 MTT assay IC5〇a REC5〇a IC5〇a ic5〇a 4hc 4hc (Nm) ( nM) (nM) (nM) % %

a : ++ : EC5〇/IC5〇&lt;l〇 nM,+ : EC5〇/IC5〇&lt;5000 ηΜ ’ -:

EC5〇/IC5〇&gt;=5000 nM

211 S 201111360

b, ++ : EC5〇/IC5〇&lt;100 nM,+ : EC5〇/IC5〇&lt;5000 nM ' -:EC5〇/IC5〇&gt;=5000 nM c : + : &gt;30% ' - : &lt;=30% 'at 1 μg/ml; "$" indicates that the test was performed at 10 μg/ml NT: untested DU937 BEAS2B DU937 (LPS) (polylC) (cell motility) IL-8 ICAM1 MTT analysis IC5〇a IC5〇a 4hc 24hc (nM) (nM) % % +5$++$+$,$+ - .+ - ++$+$$+-,+ +·++-+-+ + V... .- .V - -V. ''.·,·.. (...·::: I-------.-----:------ ^: :?..·-'··ν·:···: -.·;:ρ.一一·1?---ί:ΐ:·&quot;-;&quot;^£Ί.&quot;::··':···::::/·;:····:·····:),y;::;:-$$--$-s+s- - - - - ........ Ils#_l _ _ _ _M_lft_il3i I---------···--::::M-;:···s-:-:,a·-&quot ;.fe:':··:.:';;κ'. &quot;&quot;:·1······..':'·:.. -'.''••&quot;-....:--- ++++++-H-+ +-H-+++++++++++++++++ +NT++ --ΐ:ΐ?_s::e-&quot;ί;;::ϊ'··::--:i:s憩:;:::.e:s:ϋ. ^ ·:ϊ:·!'·:;:·. ':::...·:::κ'i::c': ;.r&quot;:·-·::: ί:.:'-.':!·:·::''::··:···ΒΚ;·::--;'.:r;:: F..&quot;&quot;· ..G···.v···········+++_ ilil-H-circle-h-_-h-:f++1+++ Ii++_t1i-h-_++ is;:'-'-;· ί·'····®&quot;··;······ ί::x.:'':'-. .v:.:ii:::-··'·:.'::;-:. -...::.···;Γ-&quot;-··:-·:·...: --:-------'-'·-··:·.. .-:·······χ;· .--:.- 〕':«-&quot;i··· ·; ί;.-:···:ίϊ::'::·:::&gt;:;;:··:·si.::i;^---·:: ί:'''·' ·'-s..i···-:···'·::ί:;::?&gt;::···· +++ t++++-H-+++++++++++ +-H-+++-H--H--l-+++++++++-H- &gt;·'.&quot; .(------- :·.'·' ··.'; :-3⁄4.--.-..一:·..'''..........--- - .''''::':'.'·'·: '·':··.···: '.'· .'· .ν·······::ν.: :--1(.1--1. ·::''·::ί ::···:-'·:v:''-:'::”·'···'···'·::ν:.-·-::''::.-:!? :r-.--.-':::·· . ';·:··:·'; ί···'·ν·· .-·'·'-:ϊ::ί:····:i:lx::::;--13⁄4s ·····--··..” .-.&quot;&quot;.------••:·····“ '..' ;|一|-s;m:ϊ5-: Ii:i:--;&quot;ft::;ii,---:;i::s#·':··:1:... :.':'·.;δ -H-++ ++i++++-H-+++++++-H-i+-H--H--H--H-++i++-H--H- »Ii«llf»«»»i:s: ++» :-:·-··;4:/1·'··.·'···.---:(3⁄4.3⁄43⁄4·:&quot;&quot;ίΒ:::'·::ϊ: ;;ii;;:-^-'·...'·'.··.·-.•&quot;? -H-+++4-++++++++++++++-l-++ +-l-++++H-++++++++ -•&quot;.&quot;•'•':·:::····ϊ:'"--··-&gt;: ·:-:·ν--·::- -------.:.--: ,--..*-. ... 1234567891011121314151617192022232426 Table 2 Example enzyme THP-1 DU937 number (LPS) ( LPS) ρ38 α ρ38 γ TNFa TNFa IC5〇a IC5〇b ICV REC5〇a (nM) (nM) (nM) (nM)

a : ++ : EC5〇/IC5〇&lt;l〇 nM,+ : EC5〇/IC5〇&lt;5000 nM,-: EC5〇/IC5〇&gt;=5000 nM

b, ++ : EC50/IC50 &lt;100 nM,+ : EC5〇/IC5〇&lt;5000 nM, -:EC5〇/IC5〇&gt;=5000 nM 212 201111360 c : + ·· &gt;30%,- : &lt;=30% at 1 μg/ml; “$,, indicates that the test is performed at 10 μg/ml NT: no test 3 cases, the code number is αα 8

V) nM

Yb 850 P3IC ps) Faoa thp (lptnic5 DU937 (LPS) TNFa RECs〇a (nM) DU937 (LPS) IL-8 IC5〇a (nM) BEAS2B DV931^ (polylC) (cell motility) ICAM1 MTT analysis 4hc 4hc 8 9 3 4 6 9 0 12 3 4 5- 6 7 9 ο- 1 2 3 4- 5 7 8 12 2 2 3 .3- 3 3- 4 4 4 4 Φ 4 4 4 Φ 5 5 5- 5 5 5 5 5 6 6 ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +-1-1- ++++++.++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ -H- ++ + ten ten NT::

NT + + :.丨丨犹:.: ++ + + + + pain; :丨:fiber++++ +丨::Mi:: +10++ + ++ ++ Ten++++, + + + -K- NT ++ ++ ++:Fiber:::: + + ++ ++ ++ ++ Edit: ++ + ++ + + +

a : ++ : EC5〇/IC5〇<l〇 nM,+ : EC5〇/IC5〇&lt;5000 nM,-: EC5〇/IC5〇&gt;=5000 nM

b,++ : EC5〇/IC5〇&lt;100 nM,+ : EC5〇/IC5〇&lt;5000 nM, -:EC5〇/IC5〇&gt;=5000 nM

S 213 201111360 C : + : &gt;30%,- : &lt;=30% at i micrograms/ml; "$,, indicating that the test is performed at 10 μg/ml NT: untested using in-vitro analysis A summary of the properties of the compound of Example 8 is presented below. The compound of Example 8 shows substantially different differences in the aspect of BIRB796. Although both compounds are induced by LPS- in THP-1 cells and differentiated U937 cells. TNFa release is a potential and potent inhibitor (Table 4), and our investigation showed that BIRB796 had no significant benefit (NSE) in the other six systems, ie, induced by LPS- in differentiated U937 cells. -8 release (BIRB796 31% maximal inhibition; Example 8 compound IC5 〇: 7.9 nM); LPS-induced IL-8 release from salivary giant scorpion cells (Table

5) ; poly I : CCAM-induced ICAM1 expression in BEAS2B cells in human bronchial epithelial cell lines (BIRB796 has no effect at 1 μg/ml; Example 8 compound ic5〇: 1.7 nM) at BEAS2B Rhesus-induced icaMI expression in cells (Table 5); rhinovirus_induced IL_8 release in BEAS2B cells (Table 2) and rhinovirus replication in MRC5 cells. In the labeled controls, the Example 8 compound demonstrated activity in all six systems and showed efficacy rates specific to or exceeding those demonstrated by LPS-induced TNFa release in U937 cells. Table 4: Comparative p38 MAP kinase activity of macrophages in BIRB 7% and Example 8 compounds and NP-a activity by LPS IC IC5 ( value (nM) 214 201111360 BIRB796 NSE@ 19μΜ (η=2) NSE @ 1 _9μΜ (n=2) NSE @ 1 ·9μΜ (η=2) p38 MAPK Enzymes LPS-induced TNFot release _ α subtype γ subtype d-U937 cells a THPl BIRB796 12 (η=6) 296 (η =5) 20 (n=2) 12 (11=3) Example 8 12 (η=2) 344 (η=2) 2.1 (n=3) 13 (n=3) a)d-U937 Cell = : Differentiation U937 cells Table 5: Comparative anti-inflammatory activity IC50 values of BIRB796 and Example 8 compounds (nM) Salivary giant sputum cells BEAS2B cell test compound induced by rhinovirus-induced rhinovirus-induced by LPS- _IL-8 release ICAM performance _IL-8 release example 8_5 (η=1)_0.37 (η=4) 0.065 (η=4) These two compounds are in human embryonic lung fibroblasts, [VJRC5 cells] The potential to inhibit rhinovirus replication has been further investigated to establish that BIRB796 is ineffective in viral replication at concentrations up to 1.9 μM. However, we studied the concentration effect curve of the compound of Example 8 and found that the concentration of 5.2 ιιΜ was reduced by a logarithmic instruction (by 1 log order). Experimental Methods Enzyme Inhibition Assay The enzyme inhibitory activity of a compound is determined by fluorescence resonance energy transfer (FRET) using a fluorophore-labeled synthetic peptide (Z-LYTE, Invert) Gold company) Determination. Briefly, the recombinant, phosphorylated Ρ38 ΜΑΡΚγ (ΜΑΡΚ12: Millipore) was diluted in HEPES buffer, mixed with humanized S.. 215 201111360 at the desired final concentration and incubated at room temperature for two hours. Next, FRET peptide (2 μΜ) and ΑΤΡ (1〇〇 _) were added to the enzyme/compound mixture and incubated for one hour. The development reagent (protease) was added to the fluorescent microplate reader one hour before detection (▽ an An沁呔 New 8 Flash, ThermoFisher Scientific). The position-specific protease only cleaves the non-phosphorylated peptide and eliminates the FRET signal. The degree of phosphorylation of each reaction is measured by the proportion of fluorescein emissions from coumarin emissions (getters), with a ratio of south indicating high linication and a low ratio indicating low phosphoric acid Degree of action. The percent inhibition of each reaction associated with the non-suppression control was calculated, and then the inhibitory concentration of 50% (IC5 〇 value) was calculated from the concentration-correspondence curve. In the case of ρ38 ΜΑΡΚα (MAPK14: Invetkin), the enzyme activity was indirectly evaluated by measuring the activation/lining of the downstream molecule, ΜΑΡΚΑΡ-Κ2. The ρ38 ΜΑΡΚα protein and its inactive target ΜΑΡΚΑΡ-Κ2 (Invitrogen) and the compound were mixed at room temperature for two hours. The FRET peptide (2 μΜ) and ΑΤΡ (10 μΜ), labeled as ΜΑΡΚΑΡ-Κ2, were then added to the enzyme/compound mixture and incubated for one hour. The development reagent is then added and the mixture is incubated for one hour prior to fluorescence detection to complete the analytical experimental procedure. LPS-induced TNFa release in U937 cells and ΤΗΡ-1 cells: potency U937 cells, human mononuclear leukocyte cell line and croton myristate acetate (PMA; 100 ng/ml) were grown up to 48 Differentiated into giant cell-type cells by 72 hours. If appropriate, the cells are pre-incubated for a period of 2 hours at the final concentration of the compound. The cells were then stimulated with 〇1 μg/home LPS (from E. coli: 0111:B4, Sigma) for 4 hours, and the supernatant was collected and sandwiched by enzymes. Immunosorbent assay (ELISA x Duo-set 'R&amp;D system) was used to determine TNFa concentration. The inhibition of the production of TNFa was calculated by comparing the concentration of the test compound with the carrier control to achieve a percentage of 10 μg/ml BIRB796. The relevant 50% effective concentration (R_Ec5q) is determined from the reaction product concentration-response curve. THP_1, the human fresh nuclear self-healing ball is also used in this analysis. THP-1 cells were stimulated with 3 μg/ml LPS (from E. coli: 0111 · B4 'Sigma (Sigma)) for 4 hours, and the supernatant was collected for determination of TNF〇t concentration. The 忒50% inhibitory concentration (IC5〇) was determined from the reaction product concentration reaction curve. [PS-induced IL-8 release in U937 cells: potency U937 cells, human mononuclear white cell line cell line with croton nutmeg, ester acetate (pMA; 100 ng/ml) for 48 to 72 Small sputum differentiates into macrophage-type cells. The cells were pre-incubated with the final/length of the compound for 2 hours. The cells were then stimulated with 〇.1 μg/ml LpS (from E. coli: 〇m: B4, Sigma) for 4 hours, and the supernatant was collected and immunized by an enzyme bond. Adsorption analysis (ELISA) (Duo-set, R&amp;D system) The IL-8 concentration was determined. Will produce IL_8 at each concentration of test compound

The inhibition of S 217 201111360 was calculated in comparison with the vehicle control group. The 5 〇 % inhibition concentration (IC50) was determined from the reaction product concentration _ reaction curve. TNF-induced TNF-alpha release in THP-1 cells: potency ΤΗΡ-1 cells, human mononuclear leukocyte cell line with 1 μg/ml LPS (from E. coli; 〇111: Β4, Sigma Stimulation for 4 hours and collection of the supernatant to determine the concentration of TNFoc by alternation (ELISA) (Duo-set, R&amp;D system). The inhibition of the production of TNFa at each concentration was calculated in comparison with the vehicle control group. The 5 〇 % inhibitory concentration (IC5 〇) was determined from the reaction product concentration _ reaction curve.

Poly I : c-induced ICAM-1 induction in BEAS2B cells: potency

Polyi: Transfect C (i μg/ml) (Invitrogen, San Diego, California) with olfactory amine (Invitrogen, Carlsbad's California) In BEAS2B cells (human bronchial epithelial cells 'ATCC). The cells were pre-incubated with the final concentration of the compound for 2 hours. The degree of expression of ICAM1 on the cell surface was determined by immunosorbent assay (ELISA) using cell-based enzyme binding. Briefly, after 18 hours of transfection with poly I : C, the cells were fixed with 4% furfural in PBS. After quenching the endogenous peroxidase with the addition of 〇 〇 〇 / 〇 azide and 1% hydrogen peroxide, the cells were washed with a wash-buffer (containing 0.1% Tween in PBS: PBS-Tween). After blocking with 5% milk in pBS-Tween in each well for 1 hour 218 201111360, the cells were treated with anti-human antibodies (Cell Signal Technology, Inc., Denver, MA) at l〇/ The medium was incubated in BSAPBS at 4 °C. The cells were washed with PBS-Tween and incubated with secondary antibody (HRP-conjugated anti-rabbit IgG' Dak〇 Ltd, Glostrup, Denmark). The signal is detected by adding a matrix and the spectrometer reading is used at 450 nm with a 65 5 nm reference wavelength. The cells were then washed with PBS-Tween and the total number of cells in each well was stained with crystal violet and eluted with a 1% SDS solution, and then taken at 5 lb. The measured 450d 450-655 readings were collected and divided by the 〇〇595 reading in each well as the number of cells. The inhibition performance of ICAM-1 at each concentration of the test compound was calculated and compared with the vehicle control group. The 5 〇% inhibition (IC50) was determined from the reaction product concentration-response curve. MTT analysis Differentiated U937 cells and compounds were pre-incubated in FCS for 4 hours or at 10% FCS for 24 hours. The supernatant was replaced with 2 liters of new medium and 10 microliters of MTT stock solution (5 mg/liter) was added to each well. The medium was removed after 1 hour of incubation, 2 liters of microliters of DMSO was added to each well and the plate was gently shaken for 1 hour before reading the absorbance at 55 Å. The percent loss associated with the carrier activity of the vehicle (0.5% DMS0) treated with each well was calculated. As a result, the cell viability of the drug treatment was significantly increased, and the carrier-related persons were listed as a negative percentage. Salivary macrophage analysis

S 219 201111360 Saliva was induced by a healthy volunteer inhaling a 3% hypertonic saline spray solution (weight/volume). Dithiothreitol (0.02% at the end) was then added and vigorously mixed using a vortex mixer until the saliva became less sticky. The pellets produced by centrifugation (at 15 rpm for 10 minutes) were resuspended in 1 〇〇/〇FCSRPMI-1640 and salivary macrophages were plated in high adhesion plates (CellBIND®, Corning, UK) ) Separate by borrowing for 2 hours. The adsorbed cells were washed with RpMI_164(R) and stimulated with LPS (1 μg/ml). After 4 hours of incubation, the supernatant was collected and assayed for IL by the enzyme-bonded immunosorbent assay development kit (R&amp;D Systems, Minneapolis, MN) using Du〇set -8 generation effect. Compounds were added 2 hours prior to lps stimulation. The rhinovirus-induced IL-8 and ICAM-1 human rhinovirus RV16 (HRV) was obtained from the American Type Culture Collection (Manassas, VA). Viral stocks are produced by infecting HeLa cells with HRV until 80% of the cells are cytopathic. BEAS2B cells were infected with 5 MOI (replicated infection 5 times) and incubated with gentle shaking at 33 ° C for 2 hours upon absorption. The cells were then washed with PBS, fresh medium was added and the cells were incubated for an additional 72 hours. The supernatant was collected and assayed for IL-8 concentration using the Dusset ELISA development kit (R&amp;D system, Minneapolis, MN). 220 201111360 The degree of expression of ICAM-1 on the cell surface was determined by the immunoassay development kit of the cell-based Duosite enzyme-bonded immunoassay kit. After appropriate incubation, the cells were fixed in 4% formaldehyde in PBS. After quenching the endogenous peroxidase with the addition of 〇 1% sodium azide and 1% ruthenium peroxide, the wells were washed with a wash-buffer (containing 0.05% Tween in PBS: PBS-Tween). After blocking for 1 hour in each well with 5% milk in PBS-Tween, the cells were incubated with anti-human ICAM-1 antibody in 5% BSA PBS-Tween (1:500). Each well was washed with PBS-Tween and incubated with a secondary antibody (HRp_conjugated anti-rabbit IgG, Dako). The signal is detected by adding a matrix and the spectrometer reading is used at 450 耄 micron with a 655 nm reference wavelength. Then, each well was washed with PBS_Tween, and the total number of cells in each well was stained with crystal violet and eluted with a 1% SDS solution, and then measured by reading the absorbance at 595 μm. The OD450-655 readings measured in each well were collected and divided by the number of holes &gt; 595 readings as the number of cells. When the non-infected HRV was washed away, the compound was added 2 hours before HRV infection and 2 hours after infection. Rhinovirus • Titration analysis MRC5 cells (human lung fibroblasts, aTCC) were infected with 1 MOI (repetitive infection) iHRV and incubated at 33 ° C for 1 hour while absorbing. The cells were then washed with pBs, fresh medium was added and the cells were incubated for an additional 96 hours. The supernatant was collected and a 1 〇-fold serial dilution of the virus containing the supernatant was prepared. Place

S 221 201111360 Some titrations were carried out by infecting a single layer of Hela cells with serial dilutions of supernatant (10-1 to 10-5) and borrowing MTT after 4 days of infection. Analysis to assess the effects of cytopathic effects. The number of viruses required to infect 50% of HeLa cells in each treatment was calculated, such as TCID50 U/ml. When the non-infected HRV was washed away, the compound was added 24 hours and 2 hours before the HRV infection and 1 hour after the infection. LPS-induced neutrophil accumulation in small mice. In the end of the LPS treatment, the mice were enrolled in the intratracheal tube with a carrier or test substance for a specified number of times (within 2-12 hours). Light administration. At T = 0, the mice were placed in an exposure chamber and exposed to LpS. Eight hours after LPS challenge, the animals were anesthetized, under the tracheal cannula, and BALF was perfused and infused through the tracheal tube into the lungs. The total number and difference of white cell counts in the BALF samples were determined using the cytotoxicity. Cell Centrifugation of BALF Samples Cytospin smears were centrifuged at 200 rpm for 5 minutes at room temperature and using the DiffQuik staining system (Dadebehlin)

It is prepared by dyeing. Cell lines were counted using an oil immersion microscope. When treated with LPS counts 2, 8 or 12 hours ago, it was found that treatment of the mice with the compound of Example 8 inhibited neutrophil accumulation in BALF (Tables 6 and 7) 12 12 hours before administration 2 hours before administration Number of neutrophils in BAL in BAL (X 105/ml) (X 10 5/ml) 20.2 ±3.7 'ml Example 8 15·1±2·1 '- 20.1 ±2.9 ml Example 8 10.4 ± 1.6 ... 16.7 ±2.4 222 201111360 14.3 ± 2.0 Ο. 2 mg / ml Example 8 | 4.6 ± 1.2 The result is average soil SEM, η = 8 shows the effect of the treatment of Example 8 Example 42 Treatment Example Carrier 8 liters [: neutrophil in BAL 16.38 ± 2.53 0.2 mg / mil 9.65 ± 1.50 Example 42 0.2 mg / ml 8.60 ± 1.59 The results were average SEM, n = 8 in guinea pigs induced by allergens Eosinophil accumulation will be immunized with Ken-Hartley guinea pigs with egg albumin. Six doses of vehicle or Example 8 (1.5 mg/ml) were administered by gas per 12 hours. The final dose was administered 2 hours prior to initiation of allergen challenge (v grade, OVA; 10 μg/ml solution) It was atomized using a De Vibliss Ultrasonic Sprayer 2000 for 30 minutes. Two groups of animals received 6 doses of Example 8, while the other two groups received 6 doses of vehicle. After 8 or 24 hours of OVA challenge (see detailed description of the previous groups), the trachea was cannulated and BALF was extracted. The method at this time included blowing 5 ml of PBS through the endotracheal tube into the lungs. The total number and difference of white cell counts in the BAL fluid samples were determined using a Noble red blood cell organ. The cytostained stained slides of the BAL fluid samples were prepared by centrifugation at 200 rpm for 5 minutes at room temperature and staining using a DiffQuik staining system (Dadebergin). The cell line was calculated using an oil immersion microscope to calculate the blind number. 223 201111360 After 8 and 24 hours of challenge with ovalbumin, it was found that guinea pigs treated with Example 8 inhibited eosinophil accumulation in BALF (Table 8). Table 8. Eosinophilic inhibition in BALF followed by allergen challenge Treatment of neutrophils in BAL (X 1〇5/ml) Neutrophil leukocytes in BAL 2 hours prior to dosing (X 1〇5/ ML) 12 hours before administration Example 8 12.4 ± 1.7 21.6 ± 3.9 Results in average soil SEM, n = 6 presentation of smoking patterns A/J. Small mice (male, 5 weeks old) using tobacco smoke inhalation experimental system for small animals (SIS-CS mode; Shibata Science and Technology Corporation, Tokyo, Sakamoto) Each exposure to cigarette smoke (4% cigarette smoke, diluted with compressed air) for 30 minutes for 11 days. After exposure to the final cigarette smoke, the test substance (containing 35 μl of the solution in 50% DMSO/PBS) was administered intranasally and twice daily for 3 days. The animals were anesthetized 12 hours after the last dose, the trachea was cannulated and the lung extract (BALF) was collected. The number of alveolar macrophages and neutrophils was determined by FACS analysis of Beckman Coulter's Fullerton, California, USA using anti-micro mouse MOMA2 antibody (macrophage) or anti-small mouse 7/ 4 antibody (neutrophil) assay. The results of treatment with Example 8 are shown in Figure 1 (neutrophils) and Figure 2 (activated alveolar macrophages). Those treated with Example 42 are shown in Figure 3 (neutrophils) and Figure 4 (activated alveolar macrophages). The number of cells is presented as an average: t SEM. The research 224 201111360 nine cigarette smoke; ^ is the corticosteroid anti-(four) system (Medi Quela S. et al. (2008), pharmacological experimental treatment journal 324 (3): 921_9) and can be confirmed Tikason (4) g is intended to inhibit the accumulation of neutrophils or giant sputum cells in the airway at % micrograms per milliliter (35 microliters of 'bld 'm) at the same dose in neutrophils induced by Lps• Accumulation yields an inhibition of &gt;80%. However, it was found that treatment with Examples 8 and 42 resulted in a reduced dose-dependent reduction in the number of labeled neutrophil &amp; ball and activated giant cells. The egg albumin-inducing/influenza-infected model of males was Ken-Hartley guinea pig (300-350 g, n=6/group) on day 2 and 6 with 1 〇〇 microgram of ovalbumin+1 〇 〇mg ai2(〇h)3 was sensitized in 1 ml of physiological saline (via the peritoneum). The parainfluenza virus (PIV-3; 1〇6 infected unit) or virus-free medium was instilled slowly on the 11th and 12th days. Animals were sprayed with (1) fluticasone propionate at a daily dose of 1.5 gram (the initial study was established at this dose of fluticasone propionate in a sensitized animal treated with PIV3 medium). Inhibition of changes in lung function as mediated by ovarian protein) or (ii) Example 8 (0.15 mg daily) or (iii) composition of Ftticasone and Example 8, using the dose indicated above or (iv The vehicle (DMSO: ethanol: saline, 30:30: 40%) was treated on days 10-15. All animals were challenged with spray OVA (10 μg/ml) on day 15 for 1 hour and repeatedly measured using a whole body volume changer at 24 hours to obtain specific airway conductivity (sGaw) ^ after 0VA challenge The measured sGaw is plotted in % as a change from the baseline. Figure 5 shows the effect of Example 8 for 225 s 201111360 as monotherapy, while Figure 6 shows the effect of administration with fluticasone propionate. When treated with Example 8, it was found that no effect was produced on the bronchoconstriction response elicited by the albumin at the beginning (1 hour), but the subsequent reaction was significantly inhibited (2-12 hours after the treatment). When co-administered with fluticasone propionate, the bronchoconstriction response caused by the excitation of _protein was inhibited both initially and later. Biological studies in vitro have shown that the compounds of the present disclosure are potent inhibitors of p38 MAP kinase subtype alpha and gamma and that test compounds show good benefits in in vitro anti-inflammatory activity patterns (including U937 cells differentiated) And LPS-induced TNFa release in ΤΗΡ-1 cells). From the results of hydrazine, it can be inferred that the test compound did not exhibit significant cytotoxicity at the concentrations used. Biological studies in the living body showed that the test compound is effective in inhibiting the accumulation of neutrophils induced by LPS-, and has a long-term effect in animal models, as shown by significant inhibition, even before administration. 8 hours. Furthermore, the 'Example 8 compound showed two surprising properties which inhibited the inflammation induced by rhinovirus and rhinovirus replication. In the context of the present specification and the following claims, unless the context requires, 'including a 'and variations' such as "comprises" and "comprising", it is understood that the meaning of the integer is included. , a group of integers or multiple steps (group 226 201111360 of steps), but does not exclude any other integers, steps, or steps. All of the patents and patent applications referred to herein are hereby incorporated by reference in their entirety. The part of the book (4) in the application (4) and the application for the patent lang: the priority is used as the basis for any subsequent request. this

Sit may: for any of the features or terms described herein, σ. It can be used in the form of products, compositions, and methods to make the scope of patents and can include examples and applications: restrictions. • [Simple description of the diagram] Figure 2 θ is not in the BALF by the smoking human white ball mode using the neutrophil accumulation of Example 8 Figure 3 * ', the member is shown in the BALF by smoking human leukocyte mode using the macrophage of Example 8 Cell accumulation ',,, page is not used in the BALF by smoking human leukocyte mode. Figure 4 I neutrophil accumulation '', not in BALF by smoking human leukocyte pattern. Figure 5 42 accumulation of macrophages sGaw value change after use of Example 8 in 0VA exposure to OVA-sensitized PIV3-infected guinea pig model 227 201111360 Figure 6 shows the use of Example 8 in OVA exposure to OVA-sensitized PIV3 infected guinea pig model And combined with Example 8 and fluticasone propionic acid sGa\v value change 228

Claims (1)

201111360, the scope of application for patents: Compound of formula (I) R1 Wherein 'R1 is d_6 alkyl' which is optionally substituted by a hydroxy group; is hydrazine or Ci_6 alkyl which is optionally substituted with a thiol group, R3 is hydrazine, d_6 alkyl or C〇_3 alkyl C3_6 ring Alkyl; Ar is a naphthyl or phenyl ring which may be optionally selected from one or more (for example, 1 or 2) independently selected from alkyl, Cl-6 alkoxy, amine, cl-4 or di- Substituted by a group of an alkylamino group; X is a 5 or 6 membered heteroaryl group containing at least one nitrogen atom and optionally including 1 or 2 other heteroatoms selected from the group consisting of 〇S and N; a) a saturated or unsaturated, branched or unbranched CM oxime bond, wherein at least one carbon (for example 1, 2 or 3 hydrazines, suitably 1 or 2, especially 1 carbon) is selected from the group consisting of hydrazine, Substituted by a hetero atom of N ' S(0)p 'wherein the chain is optionally independently selected from one or more (eg 1, 2 or 3 groups) from a keto group, a halogen, an aryl group, a heteroaryl group Substituted by a group, a heterocyclyl group or a group of a c3-8 cycloalkyl group, 229 $ 201111360 each aryl, heteroaryl, heterocyclyl or C3-8 cycloalkyl group carries 0 to 3 Selected from halogen, hydroxyl, Ci _6 alkyl, Ci_6 alkoxy, Ci-6 halo, amine, Ci_4 mono or di-alkylamino, Ci_4 mono or di-decylamino, SCCOqCK alkyl, C〇-6 alkyl C (0) a substituent of a Ci-6 alkyl or C〇_6 alkyl C(0)Ci_6 heteroalkyl group, with the proviso that the atom directly bonded to the carbonyl group in -NR3C(0)- is not oxygen or a sulfur atom; and b) C 〇 gastric octyl•heterocyclyl, the heterocyclyl group comprising at least one (eg 1, 2 or 3, suitably 1 or 2, especially 1 heteroatom) selected a hetero atom of hydrazine, N, and S, and optionally arbitrarily selected from the group consisting of halogen, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, C1 haloalkyl, amine, C1-4 Digastosyl group, Cl-4 mono or di-decylamino, S(0)qCi-6 alkyl, C〇-6 leumino C(〇) Ci_6 alkyl or C〇_6 alkyl Substituted by a C(0)Ci-6 heteroalkyl group; and P is deuterium, 1 or 2; q is deuterium, 1 or 2; pharmaceutically acceptable salts thereof, including all stereoisomers thereof' Tautomers and isotopic derivatives. 2. A compound of formula (I) according to claim 1 wherein Ar is a naphthyl group. 3. The compound of the formula (I) wherein the formula (1) or the formula (1) wherein R1 is a third butyl group. 230 201111360 4. The compound of the formula (I) of any one of claims 1 to 3 wherein R2 is a fluorenyl group. 5. The compound of the formula (I) of any one of claims 1 to 4 wherein R2 is in the para position. 6. The compound of the formula (I) according to any one of claims 1 to 5, wherein R3 is η. 7. The compound of formula (I) according to any one of claims 1 to 6, wherein NR3c(〇)Q is selected from the group consisting of: -NR3c(0)CH2〇Ci_6 alkyl, -NR3c(0)CH2〇 (CH2)2〇CH3, NR3C(0)CH(CH3)0CH3, -NR3C(0)CH2NHCH3, -NR3C(0)CH2NHCH2CH2〇CH3, -NR3C(0)CH2SCH3, -NR3C(0)NH2, _NR3C(0 CH2S(0)2CH3, -NR3c(0)NHCi_7 alkyl, -NR3C(0)N(Ci_4 alkyl)Ci_5 alkyl, and -NR3c(0)CHN[(CH2)2〇CH3]2. 8. A compound of formula (I) according to claim 7 wherein NR3C(0)Q is selected from the group consisting of: -NHC(0)CH2〇CH3, -NHC(0)CH2〇(CH2)2〇CH3, - NHC(0)CH(CH3)0CH3, -NHC(0)CH2NHCH3, -NHC(0)CH2NH(CH2)2〇CH3; -NHC(0)CH2SCH3, -NHC(0)NH2, -NHC(0)CH2S (0) 2CH3, -NHC(0)NHCH3, NHC(0)N(CH3)2, and -NHC(0)CHN[(CH2)2〇CH3]2. 231 s 201111360 9' A compound of the formula (1), wherein the compound of the formula (ΙΑ) is: Or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers and tautomers thereof. 1. In the case of the compound of the formula (I) of claim 1 of the patent, the compound of the formula (1) is: V 7 Or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers and tautomers thereof. 11. For the compound of formula (1) of the scope of patent application, the compound is ·· ' ^UC) 232 201111360 Wherein R1, r2, Ar and R3 are as defined in the first item of the patent application, and Z represents a saturated or unsaturated, branched or unbranched Ci_9 alkyl group bond, wherein at least one carbon (for example 1, 2 or 3) Carbon, suitably 1 or 2 'particularly 1' is replaced by a hetero atom selected from 0, N, S(0)p, or C〇_7 alkyl C5-6 heterocycle, the heterocyclic group The group includes at least one (eg 1, 2 or 3, suitably 1 or 2, particularly 1 heteroatom) heteroatoms selected from the group consisting of ruthenium, N and S, and optionally arbitrarily one or two or three independent Substituted with a group selected from the group consisting of halogen, Ci_6 alkyl, Ci_6 alkoxy, Ci_6-alkyl, amine, C]-4 mono- and di-alkylamino, or a pharmaceutically acceptable salt or solvent thereof Compounds, including all stereoisomers and tautomers thereof. 12. A compound of formula (I) according to claim 1 wherein the compound of formula (ID) is: 233 S 201111360 Wherein R1, r2, Ar and R3 are as defined in claim 1 and R4 and R5 independently represent hydrogen, Ci_6 alkyl, or R4 and R5 together with the nitrogen to which they are attached represent any inclusions selected from the group consisting of 〇, N and S. a 5- or 6-membered heterocyclic ring of another hetero atom, wherein the heterocyclic ring is optionally exemplified by one or two or three independently selected from the group consisting of halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 halogenate, amine, Ci_4 and Substituted by a group of a di-alkylamino group or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers and tautomers thereof. 13. A compound of formula (I) according to claim 1 wherein the compound of formula (IE) is: Among them, Rl, r2, Ar and r3 are defined as the scope of patent application! And 234 201111360 Het represents a C5-6 heterocyclic ring. The heterocyclyl group includes at least one (for example, 2 or 3 'suitably 1 or 2, particularly H-heteroatoms) selected from the group consisting of ruthenium and osmium. And a hetero atom of s, and optionally one or one or two independently selected from the group consisting of halogen, Cl-6 alkyl, alkoxy, Ci-6 haloalkyl, amine, c1-4 mono- and di-alkylamino Replaced by the group. 14_ A compound of the formula (1) as claimed in claim i, wherein the compound is selected from the group consisting of: N-(4-(4-(3-(3-t-butyl-1-l-p-phenylene)----- 〇5_yl)ureido)naphthalen-1-yloxy)°biti-2-yl)-2-(2-decyloxyethoxy)acetamide; N-(4-( 4-(3-(3-tert-butyl-1-p-phenylene-1-n-.pyran-5-yl)ureido)naphthalen-1-yloxy)D ratio °-2-yl) Tetrahydro-2H-d-decan-4-ylamine; N-(4-(4-(3-(3-tert-butyl-1-p-phenylene-m-.biazole-5-yl) Ureyl)naphthyl-1-yloxy)indole-2-yl)-2-(indolyl)acetamide; N-(4-(4-(3-(3-tert-butyl) -1-p-phenyl-lH-° than 嗤-5-yl)ureido)-n-yloxy)° ratio of -2-yl)-3-methoxypropanol; N- (4-(4-(3_(3-tert-butyl-1-p-tolyl-1H-indazol-5-yl)glycosyl)-n-yloxy)) -2-transacetic acid amine; N-(4-(4-(3-(3-isopropyl-1-p-fluorenyl-lH-atb〇)-5-yl)) -yloxy)π-biti-2-yl)-2-indoleacetic acid amine; Ν-(4-(4-(3-(3-ethyl-1-p-phenylene-1Η-pyrazole) -5-yl)ureido)naphthalenyloxy))pyridin-2-yl)-2-methoxyacetamidine Amine; S 235 201111360 N_(4-(4-(3-(3-tert-butyl-1·p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)° Bis-2-yl)-2-methoxyacetamide; N-(4-(4-(3-(3-(l-hydroxy-2-hydrylpropan-2-yl)-1-)曱Phenyl-1H-indazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)-2-methoxyacetamide; 乂(4-(4-(3) -(3-t-butyl-1-(2,3,5,6-tetraindole-4_(trimethyl)phenyl)-1Η-indazol-5-yl)ureido)naphthalene-1-氧基oxy)acridin-2-yl)-2-decyloxyacetamide; N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-. Azul-5-yl)ureido)naphthalen-1-yloxybenzidin-2-yl)-2-i-fosfoline acetamide; N-(4-(4-(3-(3-) Tributyl-1-p-tolyl-1H-indazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-ylindole dimethylamino)acetamide; (4-(4-(3-(3-tert-butyl-1-p-phenyl)-1-indole-5-yl)ureido)naphthalen-1-yloxy)π-pyridin-2- 2-(2-decyloxyethylamino)acetamide; Ν-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1Η^)-azole- 5-yl)ureido)tea-1-yloxy)π-pyridin-2-yl)-2-ylaminobenzidine, Ν-(4-(4-(3-(3-third) -1--1-p-phenylphenyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)-pyridin-2-yl)-2-(2-decyloxyethylamino) Ethylamine; Ν-(2-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-pyridin-5-yl))) Benzyloxy)pyridin-2-ylamino)-2-ketoethyl)tetrahydro sulphate; 236 201111360 N-(2-(4-(4-(3-(3-Third) Benzyl-1-p-phenyl-1H-pyrazol-5-yl)-yl)heptyl-1-yllacyl)pyranyl-2-ylamino)-2-mercaptoethyl) Indoleamine; Ν-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1-pyridin-5-yl)ureido)-n-yloxy)α咬-(2-(4-(3-(3-(3-tert-butyl)) -1-p-tolyl-1 oxime-oxazol-5-yl) fluorenyl)N- 1 -yloxy). Ϋ-(2-(4-(3-(3-tert-butyl); Ν-(2-(4-(3-(3-)-tert-butyl) -1_p-tolyl-1Η-η-biazole-5-yl)ureido)naphthalen-1-yloxy)D-pyridin-2-ylamino)-2-ketoethyl) 4-carboxyguanamine; N-(2-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-mouth-azol-5-yl))-N- 1-based lactyl). °-2-ylamino)-2-mercaptoethyl)-2,6-disorder-3-(2-(2-decyloxyethoxy)ethoxy Benzoylamine, N-(4-(4-(3-(3-tert-butyl-1-p-phenylene-1H-pyrazol-5-yl)))))唆-2-yl)-2-methyl carbarylamine, Ν·(4-(4-(3-(3-tert-butyl-1-p-phenylene-1-pyrazole-5-yl) Urea-based)-2-methylphenyl lactyl) ° bite-2-yl)-2-hydrazone-based amine, Ν-(4-(4-(3-(3-tert-butyl-) 1-p-phenylphenyl-1Η-pyrazol-5-yl)ureido)-3-indolylphenoxy)pyridin-2-yl)-2-methoxyacetamide; Ν-(4 -(4-(3-(3-tert-butyl-1-p-tolyl-1Η-η-biazole-5-yl)ureido)-2-nonyloxyphenyl)) ° ° -yl)-2-methoxyethenylamine; 237 S 201111360 N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H_) Butyryl-5-yl)ureido)-2,3-monomethylphenoxy)"»bitergic base: 2-methoxyethylamine; N-(4-(4-(3-( 3-tert-butyl-1-p-tolylpyrazole-5-yl)ureido)-3-methoxyphenoxy)acridin-2-yl)_2-methoxyacetamide; N-B --N'-4_(4-(3-(3-t-butyl-i-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalene-i-yloxy)π 唆_2. base bile; 4-(4-(3-(3-t-butyl-1-yl-p-tolyl_m_pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridine- 2-based urea; Ν-propan-2-yl-Ν'-4-(4-(3-(3·t-butyl-1-yl-p-tolyl_m_0)-pyran-5-yl)ureido Naphthyloxy)π-pyridyl-2-carbazide; 1-(3-(t-butyl)(p-phenylene)_1Η_p-zole-%)-3-(4-((2- (3-phenylureido)pyridin-4-yloxy)naphthyl)urea; 1-(4-((2-(3-indolyl))pyridyl)oxy) (3)(t-butyl)-1-(p-tolyl)-m-pyrazole-5-yl)^; 1-(4-((2-(3-cyclopropylureido)))比 斗 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Base) + (p-phenylene) 1H_pyrazole-5-yl)-3-(4-((2-(3-(2-methoxy)ethyl) Urea-based)α-pyridyl-4-(yl)naphthalen-1-yl) vein; 1-(3-(di-butyl)-1-(p-tolyl)_1Η-pyrazole_5_yl)·3- (4-((2-(3-cyclopentyl)legyl)pyridine-4-yl)oxybyl); 1-(3-(t-butyl) small (p-tolyl)·1Η_η ratio Imidazolyl)-3·(4-((2-(3-)methyl)ureido)(tetra)-4-yloxy) tea 238 201111360 2-(3-(4-(4-(3-(3) -(t-butyl)-1-(p-tolyl)-1Η-indole-5-yl)ureido)naphthalen-1-yl)oxycarbi-2-yl)ureido)ethyl acetate 4-(3-(4-(4-(3-(3-Tert-butyl-1-p-phenylene-1H-pyrazol-5-yl)) glysyl)-heptyl-1-yloxy) π 咬 基 基 基 ) ) ) ) ) ) , , , 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 4- 4- 4- 4- 1Η-oxazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)ureido)hexahydropyridine; 2-(2-methoxyethoxy)-1-( 4-(3-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1-indole-5-yl)ureido)naphthalen-1-yloxy)indole Pyridin-2-yl)yl)6-rhodium ρ-bit-1-yl) acetamidine, hydrazine-methylsulfonyl-4-(3_(4-(4-(3-(3-tert-butyl-) 1-p-phenylene _ ΙΗ-port than mouth--5-base) hiding base) Qin-1-yl Base 口 比 -2- 基 基 基 基 ) 月 -2- -2- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 5-yl)ureido)na-1-yl lactyl)吼0定_2_yl), orthoquinone-4-anthracene, N-(4-((4-(3-(3-() Tributyl)-1-(p-phenylene)-1Η-oxazol-5-yl)urea)Nylidene-1-yl)milyl)°-0-but-2-yl)-4-methyl 6 咕 咕 0 well-1-decylamine; 3- (4-(3-(3-(3-(t-butyl))-1-(p-phenylene)-1 Η-). Bizozol-5-yl) fluorenyl)-1-yl)oxy) ° bite-2-yl)-1,1-dimethyl nucleus, N-(4-((4-(3-( 3-(Tertiary butyl)-1·(p-phenylene)-1Η-α-pyrazol-5-yl) fluorenyl)distillate-1 -yl)lateyl)11-pyridyl-2-yl)hexa Rat bite-1 - anthraquinone, 239 S 201111360 N-methyl_N-(2-(morpholine-4-yl)ethyl)_Ν,-4-(4-(3·(3- Tributyl-1-p-butyryl-1Η-pyrazole-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl group; Ν-(4_(?福唯_4_基Butyl _ν'·4-(4_(3_(3_t-butyl-p-p-phenyl)-pyridin-5-yl)-ureido)naphthalen-1-yloxy)π-pyridinyl 2-based urea; Ν-(2-(m-fosyl)ethyl)_ν,-4-(4-(3-(3-tert-butyl-1-p-phenylene-lH-n) _5_yl)ureido)naphthalenyloxy)D-pyridyl-2-carbazide; NO-mercapto-isoxazole ιyl) fluorenyl-;^_4_(4_(3_(3_Third-butyl) 1_p-Phenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-ylurea; N-fluorenylmethyl)hexahydropyridin-4-yl-N' 4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-indazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl Moon urine; N-(4-(4-(3-(3-tert-butyl-1-pair) Phenyl-1H-indazol-5-yl)ureido)naphthalen-1-yloxy)°-Bis-2-yl)-4-ylhexahydropyridinium carboxycarboxamide; N-(3- (imidazol-1-yl)propyl)-N'-4_(4_(3-(3-tert-butyl-1-p-phenylene-1Η-ΒΛ°^-5-yl)ureido)naphthalene- 1-yloxy)n ratio biting 2_urea; N-(2-(3-(4-(4-(3-(3-tert-butyl-1-p-phenylene-1-)- ° ratio. sit -5_ base) treadyl) naphthalen-1-yloxy) σ than bit-2-yl) gland) ethionyl) tetrahydro port ratio; (R)_N-(4-(4 -(3_(3-tert-butyl-1·p-tolyl-1Η-carbazole-5-yl)ureido)naphthalen-1-yloxy)°°-2-yl)-3-(didecyl) Amino)tetrahydro 0-pyrrol-1-carboxyguanamine; 240 201111360 N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-.bazole-5-) ))ureido)qin-1-yloxy)°°-2-yl)tetrazosylpyrazine-1-reactive amine; 2-(3-(4-(4-(3-(3) - tert-butyl-1-p-tolyl-1 -indazol-5-yl)ureido)naphthalenyloxy)pyridin-2-yl)ureido)-indole-methylacetamide; 2-(3-(4-(4-(3-(3-Tert-butyl-1-p-tolyl-1Η-pyrazol-5-yl))-yl)-yloxy). ϋ ϋ 基 基 基 -2- -2- ) ) ) ( ( ( ( ( ( ( ( ( ( 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 1_p-Phenyl-1Η-pyrazol-5-yl)glycosyl)-1-yl lactyl) π ratio °-2-yl) fluorenyl) -(4-(4-(3-(3-tert-butyl-1-p-phenylene-1Η-吼 -5-5-yl)))) _1 _ _ ) ) ° ° _2 _2 _ base)-N-(2-(ntb σ-1,4-yl)ethyl)acetamide; Ν-(3-(1Η-imidazol-1-yl)propyl)-2-(3 -(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1-pyridin-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl Ureyl) acetamidine; 1-(2-(3-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1-indole-5-yl)) (naphthalene-1-yloxy) D-pyridin-2-yl)ureido)ethylidene)-4-methylhexazone 0 to p well; N_(3-(1H-imidazol-1-yl) Propyl)-2-(3-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl))))-naphthalen-1-yloxy Acridine-2-yl)ureido)acetamide; N-(6-(4-(3-(3-tert-butyl-1-p-phenylene-1H-pyrazol-5-yl) Urea) tea-1-yloxy)-2-methoxyethenylamine; 241 201111360 N-(6-(4-(3-(3-tert-butyl-1-p-phenylene) - 1H-pyrazol-5-yl)ureido)phenoxy)pyrimidin-4-yl)-2-methoxyacetamide; N-(4-(4-(3-(3-tert-butyl) 1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyrimidin-2-yl)-2-decyloxyacetamide; 3-(4-(4) -(3-(3-t-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyrimidin-2-yl)urea; 1-methyl -3-(4-(4-(3-(3-tert-butyl-1-p-phenylene-1H-pyrazol-5-yl))))) 2-based), 1,1-dimercapto-3-(4-(4-(3-(3-tert-butyl-1-p-tolyl-m-0)°-5-yl)脉 ) 奈 基 基 ) ) 11 定 定 定 定 定 定 定 , , , , , , , , , , , , , , , , , , , , , -1H-pyrazol-5-yl)ureido)naphthalen-1-yloxypyrimidin-2-yl)urea; (4-(4-(3-(3-tert-butyl-1-) Tolyl-1Η-η-biazole-5-yl)ureido)naphthalen-1-yloxy)pyrimidin-2-yl)fosfos-4-carboxyguanamine; 3-(6-(4-(3) -(3-t-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyrimidin-4-yl)urea; and 2-(3-( 4-(4-(3-(3-Tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl) Urea-based) acetic acid, Either a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof. 15. A compound according to claim 1 which is N-(4-(4-(3-tert-butyl-1-p-phenylene-1H-pyrazol-5-yl)urea (Naphthyl-1-yloxy)-pyridin-2-yl)-2-methoxyacetamide having the formula: 242 201111360 Or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers and tautomers thereof. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 in combination with one or more pharmaceutically acceptable diluents or carriers. 17. The compound of the formula (I) according to any one of claims 1 to 15, which is used as a pharmaceutical. A compound of the formula (I) according to any one of claims 1 to 15 or a composition according to item 16 of the patent application for treating or preventing a symptom selected from the group consisting of: COPD ( Including chronic bronchitis and emphysema), asthma, pediatric asthma, cystic fibrosis, sarcoidosis, primary pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis, allergic dermatitis Contact with dermatitis, psoriasis, ulcerative colitis, rheumatoid arthritis or osteoarthritis. Inflamed joints, rheumatoid arthritis, pancreatitis, cachexia, and inhibition of tumors including non-small cell lung cancer, breast cancer, Growth and metastasis of gastric cancer, colorectal cancer and malignant melanoma. 19. A compound of formula (I) according to any one of claims 1 to 15 or a composition of claim 16 in the manufacture of S 243 201111360 for use in the treatment or prevention of a condition selected from COPD (including chronic bronchi) Inflammation and emphysema), asthma, pediatric asthma, cystic fibrosis, sarcoidosis, primary pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis, allergic dermatitis, skin contact Inflammation, psoriasis, ulcerative colitis, rheumatoid arthritis or osteoarthritis, inflammation of the joints, rheumatoid arthritis, pancreatitis, symptoms of cachexia, inhibition of tumors including non-small cell lung cancer, breast cancer, stomach cancer The use of pharmaceuticals for the growth and metastasis of colorectal cancer and malignant melanoma. 20. A treatment selected from the group consisting of COPD (including chronic bronchitis and emphysema), asthma, pediatric asthma, cystic fibrosis, sarcoidosis, primary pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, allergies Conjunctivitis, conjunctivitis, allergic dermatitis, contact with dermatitis, psoriasis, ulcerative colitis, rheumatoid arthritis or osteoarthritis, post-inflammatory joints, rheumatoid arthritis, pancreatitis, cachexia, tumor suppression A method comprising the symptoms of growth and metastasis of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, and malignant melanoma, comprising an effective amount of any one of claims 1 to 15 (I) The compound or the pharmaceutical composition as claimed in claim 16 is administered to the individual. 244